Louisville Cardinals vs SMU Mustangs Prediction and Picks - November 22, 2025
Use Code WWWC ACC College football action on Saturday afternoon, and we have a Louisville vs SMU Prediction ready to rock and roll. Louisville checks in off a tough 20-19 home loss to Clemson, which drops them to 7-3 on the year. The Mustangs are off a 45-13 road win over Boston College to move to 7-3 on the season. These teams met last year and SMU won that game on the road by a score of 34-27. Can Louisville get revenge for that loss? Continue reading to see our Louisville vs SMU prediction.
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Cardinals Lose Heartbreaker To Clemson
Louisville comes into this matchup after a heartbreaking 20-19 loss to Clemson, a game where the Cardinals had multiple chances late but couldnāt convert. Quarterback Miller Moss threw for 212 yards on 19-of-27 passing, while adding a short rushing touchdown, but Louisvilleās offense stalled in the red zone and penalties proved costly. Running back Keyjuan Brown was a bright spot with 135 rushing yards on 15 carries, showing explosiveness against a tough Tigers front. Wideout Chris Bell led the receiving corps with 79 yards on five catches, but the Cardinals ultimately missed two potential go-ahead field goals in the final minutes.
On the season, Moss has thrown for 2,344 yards with 11 touchdowns and seven interceptions, completing 64.3% of his passes. Brown has been a steady force in the backfield with 592 yards and six scores, while Isaac Brown has added 782 rushing yards at a blistering 8.6 yards per carry. Bell remains the top target with 871 receiving yards and six touchdowns, complemented by Cory Lacyās 542 yards and two scores. Louisvilleās offense averages 31.5 points per game, but turnovers (15 on the season) have been a recurring issue. Defensively, the Cardinals have been stout, ranking 14th nationally in total defense at 297.9 yards allowed per game, with a balanced unit that limits both the run and pass.
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For Louisville, the key will be discipline and execution. Moss has shown he can move the ball efficiently, but avoiding turnovers and penalties is critical against an SMU team that thrives on offensive rhythm. Brown and Isaac Brown must establish the ground game to keep pressure off Moss, while Bell and Lacy will need to stretch the field vertically. Defensively, Louisvilleās secondary will be tested by SMUās passing attack, and their ability to generate stops on third down could swing momentum.
SMU Crushes Boston College on The Road
SMU enters this contest riding high after a dominant 45-13 win at Boston College, where quarterback Kevin Jennings threw for 326 yards and three touchdowns. Running back Tomarion Harden added 130 rushing yards on 16 carries, while wideout Yamir Knight exploded for 162 yards and a touchdown on seven receptions. The Mustangs controlled the game from start to finish, showcasing their offensive balance and ability to hit big plays through the air.
Jennings has been the catalyst all season, throwing for 2,810 yards with 21 touchdowns and nine interceptions, completing nearly 65% of his passes. Harden leads the rushing attack with 612 yards and six scores, while Cam Johnson Jr. has chipped in 316 yards and three touchdowns. The receiving corps is loaded, with Knight (460 yards, four TDs), Jordan Hudson (595 yards, four TDs), and Roderick Brinson (582 yards, three TDs) all capable of stretching defenses. SMU averages 32.2 points per game and ranks 19th nationally in passing offense, though turnovers (15 on the season) have occasionally slowed their momentum. Defensively, the Mustangs are a mixed bag: they allow 400.7 yards per game, including 298.6 through the air, but their run defense is among the nationās best at just 102.1 yards allowed per contest.
For SMU, the formula is clear: Jennings must continue to distribute the ball to his deep group of receivers, while Harden provides balance on the ground. The Mustangsā defense will be tested by Louisvilleās rushing duo, but if they can force Moss into obvious passing situations, their pass rush can take advantage. Knight and Hudson will be central to stretching Louisvilleās secondary, and if Jennings avoids turnovers, SMU has the firepower to dictate tempo. With ACC title implications still in play, the Mustangs will look to ride their offensive momentum into one of their biggest home games of the season.
Louisville vs SMU Pick
Louisville vs SMU Spread Pick
- SMU -2.5 (1 Unit)
SMU -2.5 looks like the right side because the Mustangsā offense has been consistently more explosive and balanced than Louisvilleās. Quarterback Kevin Jennings has thrown for over 2,800 yards with 21 touchdowns, and heās surrounded by a deep receiving corps led by Jordan Hudson and Yamir Knight, both capable of stretching defenses vertically. Add in Tomarion Hardenās steady production on the ground, and SMU has the kind of offensive versatility that can stress even a strong Louisville defense. The Cardinals have been stout statistically, but their offense has been turnover-prone, and Moss has shown vulnerability when forced into obvious passing situations.
Defensively, SMU matches up well because their run defense ranks among the nationās best, allowing just 102.1 yards per game. Thatās critical against Louisvilleās rushing duo of Isaac Brown and Keyjuan Brown, who have been the backbone of the Cardinalsā offense. If SMU can limit those gains and force Moss to beat them through the air, their secondary will have opportunities to capitalize. With Jennings distributing the ball to multiple playmakers and Harden keeping defenses honest, the Mustangs have the firepower and defensive structure to cover the short number at home. This sets up as a spot where SMUās offensive rhythm and run-stopping ability tilt the matchup in their favor.
Louisville vs SMU Over/Under Pick
- Over 52.5 (3 Units)
The Over 52.5 looks appealing because both offenses have shown they can put points on the board quickly, and the matchup sets up for explosive plays. SMU averages 32.2 points per game behind Kevin Jenningsā 2,800+ passing yards and a deep receiving corps led by Jordan Hudson and Yamir Knight, while Louisville counters with Miller Moss and a balanced attack that includes Isaac Brownās 782 rushing yards and Chris Bellās 871 receiving yards. The Cardinals average 31.5 points per game themselves, and while both defenses have had strong stretches, SMUās secondary has been vulnerable, giving up nearly 300 passing yards per contest. With playmakers on both sides capable of breaking games open, this feels like a matchup where sustained drives and big strikes combine to push the total past the number.
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