Gambling is not offered on this website in any form.

There is a high-quality football matchup between two AP Top 25 teams on the way as the SMU Mustangs clash with the Louisville Cardinals on Saturday afternoon. It is time to continue the NCAA Football odds series with an SMU-Louisville prediction and pick.

SMU enters the game sitting at 2-0. They pulled off a viral upset over the Florida State Seminoles on the road. This happened after the opener had a delay due to power outages on FSU's campus and football stadium. They followed that up with a dominant 53-10 win over UC Davis in Week 2, showing the Mustangs' explosiveness on both sides of the ball.

Meanwhile, Louisville is 1-1 at the moment. They opened the season against Ole Miss. The Cardinals valiantly competed with the Ole Miss Rebels, who made the semifinals of the 2025-26 College Football Playoffs. Despite their efforts, they lost the season opener in a 41-38 nailbiter. Louisville got back on track with a dominant 59-13 rout over the Villanova Wildcats in Week 2. However, they have another chance to get a ranked win in their upcoming clash with SMU.

SMU and Louisville have met four times prior to this football game, with SMU winning all four contests.  The Mustangs dominated the Cardinals in a 38-6 blowout in 2025.

Odds provided by BetOnline

SMU vs. Louisville Odds

SMU: -1.5 (-113)

Louisville: +1.5 (-107)

Over: 58.5 (-110)

Under: 58.5 (-110)

SMU vs. Louisville Key Injuries

SMU- RB EJ Kelly (Probable), RB Link Rhodes (Out), RB Christian Rhodes (Questionable), TE Miles Uter (Questionable).

Louisville- WR Payton Cook (Out), RB Keyjuan Brown (Questionable), OG Anwar O'Neal (Questionable), WR Montavin Quisenberry (Out), WR Kris Hughes (Out).

Article Continues Below

SMU vs. Louisville Betting Trends

  • Over is 4-0 in Cardinals last 4 games after allowing less than 20 points in their previous game.

  • Mustangs are 6-1 ATS in their last 7 games overall.

  • Over is 4-0 in Cardinals last 4 games in September.

  • Mustangs are 5-1 ATS in their last 6 games as a favorite.

  • Cardinals are 8-2 ATS in their last 10 home games vs. a team with a winning road record.

Keys to SMU vs. Louisville matchup

Kevin Jennings has posted a record of 21-7 as the starter for the Mustangs; the 21 wins are tied for the second most by a returning Power 4 quarterback. Jennings is the ACC active leader in career passing yards (8,476) and career total yards (9,072). This season, he has completed 40 out of 52 passes for 767 yards and eight touchdowns. Kendrick Raphael leads rushers with 15 carries for 78 net yards and a touchdown. Four receivers are over 100 yards each two games in, seeing Yannick Smith lead the group with six catches for 151 yards and two touchdowns.

On defense, SMU has done a solid job at delivering in big moments to secure valuable wins. They recorded 129 sacks since 2023, the most in all FBS during that span. Since 2024, the Mustangs have forced 53 turnovers, which ranks tied for seventh most in the in country during that span and tied for first in the ACC. This season, Tyren Polley Jr. leads the side with 11 tackles while Jimmy Wyrick has 11 tackles and two sacks to his name.

Louisville needs to be able to hit the big plays in this one, especially on defense. Lincoln Kienholz needs to set the offensive tone with his play at quarterback, delivering huge passes in critical moments. This season, he has completed 34 out of 50 passes for 639 yards and four touchdowns. Kienholz has also been active in the run game, racking up 20 carries for 111 net yards and three touchdowns. Isaac Brown comes next with 12 rushes for 97 net yards, while Marquise Davis has two rushing scores to his name. Tre Richardson leads the receiving corps with 11 catches for 181 yards and a touchdown, Lawayne McCoy has five receptions for 164 yards and two touchdowns, while Jaleel Skinner caught five passes for 137 yards and a touchdown.

On defense, it is all about the combination of Koen Entringer, Kaleb Beasley and Stanquan Clark that will make the difference. Entringer leads the defensive side of the ball with 12 tackles and one TFL. Beasley follows suit with 11 tackles and a pass breakup, while Clark made an interception and broke up two passes.

SMU vs. Louisville Prediction and Pick

This ranked matchup will be an entertaining one for football fans who dedicate time to games involving both teams in the AP Top 25 rankings. SMU has the momentum in its favor but will have a tough challenge with handling a hostile crowd. Louisville showed they are no pushovers against Ole Miss, meaning the Mustangs can't take them lightly throughout the course of the game. Regardless, the contest will present entertaining moments for attending fans. Louisville gets the win in this football contest and covers, while the under also hits.

Final SMU vs. Louisville Prediction and Pick: Louisville +1.5 (-107) and under 58.5 (-110)