The Louisville Cardinals take on the SMU Mustangs in Dallas, Texas. Kickoff is set for 12:00 p.m. EST on ESPN2.
SMU is favored by 2.5 points on the spread with a moneyline of -140. The total is set at 52 points.
Here’s my Louisville vs. SMU prediction and college football picks for Saturday, November 22, 2025.
Louisville vs SMU Prediction
- Louisville vs. SMU Pick: SMU -3.5 or Better
Louisville vs SMU Odds
| Cardinals Odds | ||
|---|---|---|
| Spread | Total | Moneyline |
+2.5 -105 | 52 -110o / -110u | +120 |
| Mustangs Odds | ||
|---|---|---|
| Spread | Total | Moneyline |
-2.5 -115 | 52 -110o / -110u | -140 |
- Louisville vs SMU point spread: SMU -2.5
- Louisville vs SMU over/under: 52.5
- Louisville vs SMU moneyline: Louisville +120, SMU -140
Louisville vs SMU Preview
One of the best situational spots for Week 13 comes in the ACC, where SMU will have some extra rest off a bye week.
Louisville not only has to travel to Texas after back-to-back losses, but it must regroup after a heartbreaking 20-19 defeat at the hands of Clemson before a rivalry game against Kentucky in Week 14.
On the other side, SMU is live to make the ACC Championship.
The Mustangs must win their final two games against Louisville and Cal while also needing help from the other ACC contenders to make it to Charlotte for the conference title game.
SMU has won five of its last six games, picking up a victory in every conference game at home this season.
The defense has been the strong point for the Mustangs, ranking in the top 15 nationally in Havoc, Tackling, and Finishing Drives allowed.
Meanwhile, Louisville has struggled on offense throughout the season, as the offensive line sits outside the top 100 in Line Yards and Stuff Rate.
Stuff Rate — the measurement of owning the line of scrimmage — has been a disaster for the Cardinals, who own a rank of 125th out of all FBS teams.
Offensively, SMU's rushing attack will put it in scoring position against a Louisville defense that gives up plenty of explosive plays on the ground. Mustang running backs TJ Harden and Chris Johnson Jr. have racked up 19 explosives on the season.
Look for a well-rested SMU team to push toward another ACC Championship appearance, as Louisville continues to struggle to finish games.
Pick: SMU -3.5 or Better
