Louisville vs. Ole Miss Picks Today: Prediction, Props and Best Bets for Sunday (Sept. 6)

Louisville vs. Ole Miss Picks in Summary

• Louisville +6.5 (+100)
• Under 54.5 (-105)

One of the most intriguing matchups of college football's opening weekend takes place Sunday night in Nashville, where No. 24 Louisville takes on No. 9 Ole Miss in the Music City Kickoff.

Ole Miss enters the season with legitimate College Football Playoff expectations after going 13-2 and reaching the CFP semifinal last season. The Rebels return quarterback Trinidad Chambliss and star running back Kewan Lacy, who combined for more than 5,500 yards of offense in 2025.

Louisville is no slouch, though. The Cardinals went 9-4 last season and return explosive running back Isaac Brown while adding Ohio State transfer Lincoln Kienholz at quarterback.

Using the college football odds at FanDuel Sportsbook as a guide, here are the best bets for this game.

All college football odds come from FanDuel Sportsbook and may change after this article is published.

Mississippi vs Louisville Prediction and Picks

Louisville +6.5 (+100)

I like the Louisville Cardinals to keep this game within a touchdown.

The Mississippi Rebels are clearly the more proven team coming off a 13-2 season, but this line is asking the Rebels to win by a full touchdown in a neutral-site game. The Cardinals went 9-4 last season and averaged 29.9 points per game while generating 384.5 yards per contest. They can play.

Louisville also has a legitimate difference-maker in the backfield. Isaac Brown averaged an incredible 8.8 yards per carry last season, rushing for 884 yards on only 101 attempts before missing the latter part of the year with an injury. He's healthy entering 2026 and should give Louisville a way to attack an Ole Miss defense that allowed 149.1 rushing yards per game last season.

The quarterback question is the biggest concern for Louisville, as Kienholz is taking over after spending the past two seasons at Ohio State. But Cards coach Jeff Brohm has had considerable success developing quarterbacks, and Louisville's offensive line has been rebuilt with 142 career starts of experience.

Ole Miss has plenty of firepower, but the Rebels also have a new offensive coordinator and defensive coordinator after last season's run. Chambliss and Lacy give them a tremendous foundation, yet Louisville's experienced linebacker group and returning playmakers on defense should make this a tough matchup.

I'm expecting a competitive game from start to finish. Give me Louisville +6.5.

Under 54.5 (-105)

I'm also leaning toward the under.

Ole Miss averaged an impressive 36.9 points per game last season, but this is a new season and the Rebels are dealing with changes to the coaching staff. Chambliss returns, which is enormous, but the offense will now operate under offensive coordinator John David Baker.

Louisville's defense is well-equipped to slow down an opponent that wants to establish the run. The Cardinals allowed just 114.3 rushing yards per game last season, and they return several important pieces, including Stanquan Clark, T.J. Capers and Antonio Watts.

That matchup is particularly important because Lacy was the centerpiece of Ole Miss' offense in 2025. He rushed for 1,567 yards and 24 touchdowns on 306 attempts, establishing program records in both rushing attempts and rushing touchdowns. Louisville is going to devote plenty of attention to stopping him.

On the other side, Ole Miss allowed only 21.1 points per game last season and is returning a defense loaded with playmakers, including linebacker Suntarine Perkins. Louisville could struggle to consistently finish drives with touchdowns while breaking in a new quarterback.

While there is talent on both offenses, I think the defenses can do enough to keep this game under 54.5 points.

College Football Betting FAQ

What are the most common college football bets?

The most common college football bets are the point spread, moneyline, and game total. Bettors can also wager on player props, team totals, alternate spreads, and futures such as conference champions or the national championship winner.

How does the point spread work in college football betting?

The point spread gives one team a handicap to create a more even betting market. If a team is listed at -7.5, it must win by at least eight points for a spread bet on that team to cash. A team listed at +7.5 can lose by seven points or fewer — or win outright — and still cover the spread.

What does over/under mean in college football?

An over/under, also called a game total, is a wager on the combined number of points scored by both teams. Bettors can choose whether the final score will finish over or under the sportsbook's posted total.

What should you consider before betting on college football?

Matchups, quarterback play, offensive and defensive efficiency, injuries, pace, home-field advantage, and coaching tendencies can all be important.

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The above author is a FanDuel employee and is not eligible to compete in public daily fantasy contests or place sports betting wagers on FanDuel. The advice provided by the author does not necessarily represent the views of FanDuel. Taking the author's advice will not guarantee a successful outcome. You should use your own judgment when participating in daily fantasy contests or placing sports wagers.