With the Louisville Cardinals’ season opener just a few weeks away, it’s time to take a closer look at the 2025 schedule—one game at a time. Fans have spent the offseason projecting how far this team can go, and as kickoff approaches, the excitement is building in a big way.
A major reason for that optimism is the arrival of transfer quarterback Miller Moss. As good as Tyler Shough was last season, Moss brings even more upside and is expected to elevate Jeff Brohm’s offense from day one. Add in the return of 2024 breakout running back Isaac Brown, and the Cardinals appear poised to light up the scoreboard again this fall.
Now in his third season as head coach, Jeff Brohm has a roster capable of making another run at the ACC Championship. With a manageable schedule and explosive playmakers on both sides of the ball, the opportunity is there.
Here’s a game-by-game prediction of how the 2025 season could unfold—and what it will take for Louisville football to return to the ACC title game.
Week 1: vs Eastern Kentucky (Aug 30th)
Louisville opens the 2025 season at home against Eastern Kentucky in what should be a comfortable start to the year. The Colonels are coming off a respectable 8–5 season and an FCS playoff appearance, and they return some strength on defense—most notably All-American defensive back Jaheim Ward and a veteran front seven featuring Gabe Fletcher and Jeremiah Bailey.
Still, the gap in depth, speed, and overall talent will be hard for EKU to overcome. Louisville’s offense, now led by USC transfer Miller Moss, should get off to a fast start. He’ll have plenty of help in Jeff Brohm’s system, with a strong running game and a deep group of receivers ready to make plays. This game offers the perfect opportunity for Moss to get comfortable under center and for the offense to find its rhythm early.
EKU will be breaking in a new quarterback, senior Ron Vann Jr., who makes his first career start against a Louisville defense expected to be faster and more aggressive than what he’s used to. Expect the Cards to take control early and empty the bench in the second half.
Prediction: W (1-0) Louisville 45 - Eastern Kentucky 10
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Week 2: vs James Madison (Sep. 5)
James Madison comes to town for a Friday night clash as Louisville takes on a tougher test in Week 2. The Dukes are coming off a strong 9–4 season that included a high-scoring upset over North Carolina and a bowl game victory to close out the year.
JMU returns key playmakers, including standout running back George Pettaway, and boasts two additional players who earned preseason All-Sun Belt honors. The Dukes are looking to build on last year’s success and continue their rise as one of the top programs in the Group of Five.
Known for their physical, hard-nosed brand of football, James Madison won’t make things easy. Still, Louisville holds a clear advantage in overall talent and depth. This game will be a noticeable step up from the opener against Eastern Kentucky, but it’s also an opportunity for Miller Moss to settle in and get comfortable in Jeff Brohm’s offense.
If the Cardinals can take care of the ball and win the battle in the trenches, they should be able to pull away and move to 2–0 on the season.
Prediction: W (2-0) Louisville 31- James Madison 17
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Week 3: vs Bowling Green (Sep. 20th)
Louisville stays home for Week 3 to face Bowling Green in the first-ever meeting between the two programs. While the Falcons have been a solid MAC team under head coach Scot Loeffler, this matchup heavily favors the Cardinals—especially in the trenches.
Jeff Brohm coached against Bowling Green when he was the head coach at Western Kentucky back in 2014 and won 59-31. He will look to have similar success, probably focusing on a BG run defense that struggled in 2024, allowing over 168 yards per game and 4.7 yards per carry overall—and more than 210 yards per game against non-conference opponents. That spells trouble against a Louisville offense featuring Isaac Brown, who’s poised for a big year behind an experienced offensive line. Expect Jeff Brohm to lean on the ground game early and often, getting plenty of other running backs in the mix like Keyjuan Brown and Duke Watson, then allowing Miller Moss to settle in and build rhythm through play-action and high-percentage throws.
Defensively, Louisville should be able to control the line of scrimmage and limit big plays, forcing Bowling Green into third-and-long situations where they’ve struggled to stay on the field.
This is another game where the Cardinals’ depth and talent will be the difference. It may stay competitive early, but Louisville should pull away before halftime and cruise to 3–0
Prediction: W (3-0) Louisville 35 - Bowling Green 17
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Week 4: at Pittsburgh (Sep. 27th)
Louisville hits the road for a primetime showdown in Pittsburgh—a venue where the Cardinals have often struggled. Louisville has struggled in away games at Pitt, with losses in all three games at Pittsburgh since 2015. Last year’s 37–9 blowout win at home demonstrates Louisville’s capability when firing on all cylinders, and with Pitt projected as a middle of the pack team, with Louisville projected as a top of conference team, hopefully something more like last year’s result is expected this year.
Pittsburgh brings a disruptive defense—ranked top ten in the FBS last year in tackles for loss and sacks—making them a formidable defensive front. Still, Louisville should lean into their offensive strengths. A healthy, confident Miller Moss getting the ball out quick and connecting with explosive pass-catchers, such as Chris Bell and Caullin Lacy, will keep the offense moving forward. Not to mention relying on a run game that should be well established by this point in the season.
Defensively, Louisville must control the line and minimize mistakes—Pitt thrives on chaos and pressure. If the Cards establish tempo early and avoid penalties, they can stay ahead of the Panther’s disruption.
Given Louisville’s momentum and depth, a road win is likely—but expect a competitive first half. Don’t be surprised if Louisville puts it away in the third quarter.
Prediction: W (4-0) Louisville 31 - Pittsburgh 17
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Week 5: vs Virginia (Oct. 4th)
Louisville returns home after the road trip to Pittsburgh to host Virginia—a program known for its methodical pace and defensive discipline. In recent years, the Cavaliers have developed into a tough ACC matchup, leaning on winning in the trenches and slowing the game down against better opponents. They have also recently ranked in the top half of the ACC in sacks and third-down defense.
On paper, Louisville may have the edge. Miller Moss has established chemistry with his weapons—Chris Bell, Caullin Lacy, and the newcomer TreyShun Hurry—while Isaac Brown continues to assert himself as one of the ACC’s most impactful running backs.
Defensively, linebacker veterans who anchor the Cardinals’ front seven such as TJ Quinn and Stanquan Clark, should disrupt Virginia’s rhythm. That said, Virginia’s offense is no pushover, featuring a run-heavy attack and physical offensive line. Louisville must avoid getting entangled in slow-down tactics or long drives. If the Cards play fast, limit mistakes, and capitalize on explosive plays, they’ll pull away in the second half.
Expect a balanced, competitive first half, but with their depth and talent, Louisville should pull away late.
Prediction: W (5-0) Louisville 35 - Virginia 21
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Week 6: at Miami (October 17th)
Louisville hits the road for perhaps its toughest challenge yet: a Friday night lights showdown at Miami. Historically, the series favors the Hurricanes—Miami leads 12–4–1 and edged Louisville in their shoot out last season.
While the Hurricanes lost a lot from their number 1 ranked offense in 2024, they should still be able to put up big numbers in 2025. Georgia transfer QB Carson Beck brings his experience and proven stats with over 7,900 years and 58 TDs in his career as a passer. Beck along with a highly touted running back room of Mark Fletcher Jr and Jordan Lyle will be more than enough to make defenses scratch their heads on a weekly basis.
Louisville will do it’s best to win in Miami for a second consecutive time after winning the 2023 offensive explosion. With a bye week before this game, look for Brohm and co-defensive coordinators Ron English and Mark Hagen to spend plenty of time and energy to try to figure out this Hurricane’s offense.
If the game was in Louisville this year, they may have gotten the nod, but with it being away, the edge goes to Miami as they will hand the Cardinals their first loss of the season.
Prediction: L (5-1) Miami 38 - Louisville 31
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Week 7: vs Boston College (Oct. 25th)
When Louisville faces Boston College this fall, they’ll be taking on a retooled Eagles squad in Year 2 under head coach Bill O’Brien. The biggest difference from last year? BC no longer has dual-threat quarterback Thomas Castellanos, who gave the Cardinals fits in 2023. In his place is Alabama transfer Dylan Lonergan, a former four-star recruit with a big arm but limited experience.
Offensively, the Eagles still want to lean on the ground game. They rushed for over 160 yards per game last year and return key offensive line pieces to support that identity. Louisville’s front seven—anchored by linebackers Quinn and Clark—should be ready for the challenge, especially with edge rushers like Mason Reiger returning.
Defensively, BC loses standout pass rusher Donovan Ezeiruaku, which could make things easier for Miller Moss and Louisville’s high-powered offense. With too many returning weapons like WR Chris Bell and RB Isaac Brown, the Cards should have too much firepower, especially at home.
Again, if this game was in Boston, it would be harder to pick the Cards with such confidence, but at home Louisville should take care of the Eagles with ease.
Prediction: W (6-1) Louisville 31 - Boston College 21
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Week 8: at Virginia Tech (Nov. 1st)
Virginia Tech enters this game as a much-improved team from 2024 after finishing 7–6 last season. The Hokies return dual-threat quarterback Kyron Drones, who totaled over 2,500 yards and 22 touchdowns, and they bring back several key weapons, including receiver Ayden Greene and a veteran offensive line. Defensively, the Hokies are led by linebacker Jaden Keller and defensive tackle Kemari Copeland, forming a front seven capable of slowing down most ACC opponents.
Louisville, though, has the advantage in offensive firepower. Quarterback Miller Moss should have time behind a solid offensive line to spread the ball to his favorite targets and work off of the run game.. The Cardinals will look to establish that run game early with Isaac Brown, which could open up play-action opportunities against an aggressive front seven.
The biggest challenge for Louisville will be containing Drones, particularly when he escapes the pocket. But the Cards' defense is experienced and should keep his legs in check more often than not, forcing him to beat them with his arm. A close game, but Cards find a way.
Prediction: W (7-1) Louisville 28 - Virginia Tech 24
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Week 9: vs California (Nov. 8th)
California makes the long trip to Louisville for this rare ACC matchup, entering 2025 with tempered expectations after a 6–7 record last year. The Golden Bears return starting quarterback Fernando Mendoza, who threw for over 2,200 yards and 14 touchdowns in 2024. Cal’s offense also features veteran receiver Trond Grizzell and running back Jaydn Ott, a dynamic threat who posted over 1,200 scrimmage yards last season.
Defensively, Cal struggled last year, finishing near the bottom of the Power Five in total defense (allowing 417 yards per game). While linebacker Kaleb Elarms-Orr returns as a leader in the middle, questions remain in the secondary and overall depth.
The Louisville offense behind Miller, Bell and Brown should pick up right where they have been all season long and overpower Cal in this one.
Prediction: W (8-1) Louisville 38 - Cal 17
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Week 10: vs Clemson (Nov. 14th)
In what will be their third Friday game of the year, Louisville will host Clemson at L&N Stadium come mid-November. Clemson comes to Louisville as a perennial ACC power, as even in what was considered a “down year” in 2024, they went 10–3, finishing second in the ACC, and won the ACC Championship.
Star quarterback Cade Klubnik returns for his senior season and will hope to improve on what was a pretty mediocre year for him (2,739 yards 19 TDs and 10 INTs). The top pass catcher and running back from 2024 each have moved on, but Klubnik will still have plenty of talent around him.
Even with a playoff- experienced QB, the real strength of this Clemson Tiger’s team is their defense. Clemson’s front seven is nasty again, headlined by Peter Woods and T.J. Parker. The secondary is one of the best in the country, with Avieon Terrell and Kylon Griffin anchoring it.
The Louisville offense will have its hands full, and have to play extremely mistake free in order to hand Clemson its second upset loss in two years in this new ACC rivalry.
Prediction: L (8-2) Clemson 27 - Louisville 17
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Week 11: at SMU (Nov. 22nd)
As under-the-radar as SMU was in 2024 before their surprising College Football Playoff run, they enter 2025 with a national spotlight squarely on them. The Mustangs went 11-3 in their first ACC season, largely behind the breakout performance of quarterback Kevin Jennings, who totaled over 3,500 yards and 28 touchdowns with both his arm and legs. Jennings returns with Heisman buzz, and expectations are sky-high in Dallas.
A big reason for SMU’s continued optimism is their offensive line, which returns the majority of its starters. That continuity should help the Mustangs replicate — or even improve on — last year’s offensive output. If not for a tough playoff showing, Jennings might be viewed as a frontrunner for the Heisman, and SMU might be seen as the ACC favorite.
Louisville, meanwhile, will be looking to avenge last season’s one-score home loss to SMU. This year’s matchup could again come down to a single possession or a game-changing play. Whether it’s a last-minute drive by Miller Moss and the offense, or a fourth-quarter stop from the defense, the Cardinals will need to deliver in the clutch to pull off a critical ACC win.
Prediction: W (9-2) Louisville 27 - SMU 24
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Week 12: vs Kentucky (Nov. 29th)
Kentucky enters the 2025 season with a projected win total of 4.5, following a disappointing 4-8 (1-7 SEC) campaign last year. It was a tough season for head coach Mark Stoops, who now looks to regroup and rebuild. One area of focus is the offense, where graduate transfer quarterback Zach Calzada brings a glimmer of hope. Though he arrives from Incarnate Word, Calzada has prior SEC experience and will need to quickly adjust to the speed and physicality of the league once again.
With an upgraded quarterback room and renewed emphasis on solidifying the offensive line, there’s cautious optimism that the Wildcats can take a step forward. One game already circled on the schedule is the Governor’s Cup matchup against Louisville. After falling to the Cardinals last season, Kentucky will be eager for revenge.
However, if the season unfolds as many predict, Louisville should be in position to take care of business once again. For the Cardinals, the formula is simple: take care of the football, control the clock, and execute efficiently. Do that, and they’ll likely claim their second straight win in the rivalry.
Prediction: W (10-2) Louisville 41 - Kentucky 10