Louisville Cardinals vs SMU Mustangs Prediction, Odds and Picks for Saturday, 11/22/25

We have a fascinating contest on our hands on Saturday as the Louisville Cardinals will face off against the SMU Mustangs in a clash between a couple of ACC sides heading in opposite directions. This is a terrific situational spot for SMU as Rhett Lashlee’s team is coming off a bye following an impressive showing against Boston College the week before. The Mustangs are live to make the ACC Championship and they’ll need to win their final couple of games against Louisville and California in order to stay alive in the race for a potential playoff berth. Despite getting off to a pretty slow start, the Mustangs have quietly won 5 of their last 6 games and has been especially solid at home, where they’ll catch a Louisville team that is entering this game following back-to-back crushing losses against California and Clemson by a combined 4 points. The Cardinals are now firmly out of the ACC title game picture after looking like the team to beat in the conference just a few weeks ago. With that in mind, a trip to Texas to face a well-rested SMU team is not exactly an easy task for Jeff Brohm and company.

Even setting aside the spot, it’s not as if the Louisville offense has been lighting the world on fire in recent weeks. Miller Moss has struggled under center and the Cardinals typically reliable ground attack has stalled out with running back Isaac Brown out of the lineup. That doesn’t bode well against an SMU defensive front that has tons of talent and has been excellent against the run to this point in the season (21st in rushing success rate allowed, 10th in EPA per rush allowed, 17th in Early Downs EPA). Louisville is not a team that is built to rally from behind, so if Kevin Jennings and the strong SMU rushing attack can get on the board early against a shaky Cardinals rush defense, this is a spot where things could unravel for a Louisville team that is in free-fall at the moment. Ultimately, the Mustangs are the only way I can look in this matchup.

Louisville vs SMU prediction: SMU -2.5 available at time of publishing. Playable at that number.

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