Louisville vs. SMU Prediction, Odds and Key Players to Watch for College Football Week 13

Iain MacMillan | Nov 20, 2025

Louisville is a road underdog against SMU in Week 12 college football action. / Matt Stone/Courier Journal / USA TODAY NETWORK via Imagn Images

The Louisville Cardinals were in a great spot to secure a berth in the ACC Championship, but their dreams have been dashed by back-to-back losses to California and Clemson. Now, they hit the road to take on a SMU Mustangs team that is one of just four teams left in the ACC with a single conference loss.

Let's dive into the odds and my best bet for Saturday afternoon's matchup.

Louisville vs. SMU Odds, Spread, and Total

Odds via FanDuel Sportsbook

Spread

• Louisville +3.5 (-114)
• SMU -3.5 (-106)

Moneyline

• Louisville +134
• SMU -162

Total

• OVER 53.5 (-110)
• UNDER 53.5 (-110)

Louisville vs. SMU How to Watch

• Date: Saturday, Nov. 22
• Game Time: 12:00 pm ET
• Venue: Gerald J. Ford Stadium
• How to Watch (TV): ESPN2
• Louisville Record: 7-3 (4-3 in ACC)
• SMU Record: 7-3 (5-1 in ACC)

Louisville vs. SMU Betting Trends

• Louisville is 3-7 ATS this season
• Louisville is 7-1 straight up in its last eight road games
• The UNDER is 4-2 in Louisville's last six games
• SMU is 4-1 ATS in its last five games
• The UNDER is 6-2 in SMU's last eight games
• SMU is 18-2 straight up in its last 20 home games

Louisville vs. SMU Prediction and Pick

• Keyjuan Brown, RB - Louisville Cardinals

A big reason for Louisville's two-game losing streak is because of an injury to its star running back, Isaac Brown, who has been sidelined with an injury the past few weeks. The good news is Keyjuan Brown has done a solid job in his place, averaging 7.3 yards per carry, but even that is nowhere near Isaac's average of 8.6 yards per carry. Brown will need to have another solid performance on Saturday if the Cardinals want to upset the Mustangs.

Louisville vs. SMU Prediction and Pick

Don't let their two recent losses fool you, this Louisville Cardinals team is still one of the best teams the ACC has to offer. The Cardinals enter Week 13 ranking 23rd in the country in adjusted net EPA per play, while the Mustangs rank 34th in that metric.

Expect both quarterbacks in this game to have a heavy workload. SMU and Louisville rank 19th and 21st in passing play percentage, with over 54% of their plays being pass plays. That's great news for the Cardinals, who have the far superior pass defense. Louisville ranks 12th in opponent dropback EPA, while SMU ranks 50th in that metric.

The stylistic advantage goes to the Cardinals, so I'll take the points with Louisville in this ACC showdown.

Pick: Louisville +3.5 (-114) via FanDuel

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