Ole Miss vs. Louisville prediction, odds, pick for top-25 battle in Week 1

Ole Miss travels to Nashville in Week 1 of the college football season to face off against Louisville. Both teams come in ranked for this Sunday evening matchup in the Music City. It is time to continue the NCAA Football odds series with an Ole Miss-Louisvilleprediction and pick.

Ole Miss enters the season ranked ninth in the AP Poll and tenth in the Coaches Poll. In 2025, Ole Miss got off to a hot start, opening up the season 6-0 and moving into the top 5 of the AP Poll. They would then take a loss on the road to Georgia, but the team would rebound to win their last five games. With the head-to-head loss to Georgia, Ole Miss did not make the SEC championship game, but still made the playoffs. Before the College Football Playoffs, Lane Kiffin would depart for LSU, leaving Pete Golding in charge for the postseason run. Ole Miss dominated Tulane in the first round, before taking out Georgia in the quarterfinal. The run would end in the Fiesta Bowl with a 31-27 loss to Miami.

Meanwhile, Louisville comes into the game ranked 24th in the AP Poll, but was not ranked in the Coaches Poll. Louisville opened the 2025 season 4-0 before a loss at home in overtime to Virginia. They would then win three more, including upsetting number-two-ranked Miami on the road. Still, three straight losses, including an overtime loss to Cal and a one-point loss to Clemson, both at home, took them out of contention in the ACC and dropped them out of the Top 25. They would end the season in the Boca Raton Bowl, defeating Toledo 27-22.

This will be just the second time that Louisville and Ole Miss have faced off. The two went head-to-head in Atlanta to open the season in 2021, with Ole Miss taking the 43-24 victory. Odds provided by DraftKings

Ole Miss vs. Louisville Odds

Ole Miss: -6.5 (-118)

Louisville: +6.5 (-102)

Over: 55.5 (-105)

Under: 55.5 (-115)

Ole Miss vs. Louisville State Key Injuries

Ole Miss-  None

Louisville- RB Marquise David (Questionable), RB Isaac Brown (Probable), WR Kahlil Hughes (Out), WR Montavian Quisenberry (Out)

Ole Miss vs. Louisville State Betting Trends

– Ole Miss was 9-6 against the spread in 2025, but covered in three of their last four games.

– Ole Miss covered seven out of the 11 times they were a favorite last season.

– The over hit in eight Ole Miss games last season, including both times at a neutral site.

– Louisville was just 4-9 against the spread in 2025, and covered just once in their final five weeks.

– Louisville was 1-1 against the spread as an underdog last year. In the game they covered, they won outright over Miami.

– The under hit in seven of Louisville’s 13 games last year, including in their only neutral-site game.

Keys to Ole Miss vs. Louisville matchup

For Ole Miss, it starts with breaking in a new group of receivers. The Rebels bring back Trinidad Chamliss, who passed for 3,937 yards with 22 touchdowns last year. He also ran for 527 yards and eight scores. Meanwhile, the defense will be kept honest not only by his running ability, but by the fact that Kewan Lacy is back after running for 1,567 yards and 24 touchdowns. Still, of their top six pass catchers last just, just one returns, which is Deuce Alexander. Darrell Gill Jr. comes in from Syracuse after back-to-back 500-plus-yard seasons. His teammate from Syracuse last season, Jontay Cook II, joins the team as well, after bringing in 549 yards and two touchdowns.

On defense, it will be about stopping the big play. Issac Brown ran for 884 yards in just nine games, and averaged 8.8 yards per carry. The big-play running back also had 11 carries of 20 or more yards, including a 78-yarder against James Madison, a 73-yarder against Boston College, and two other 50-yard runs. Louisville also brought in Lincoln Kienholz from Ohio State to be the quarterback. He played in seven games last year and was solid, completing 11 of 14 passes, while also running 11 times for 66 yards and two scores. His legs will be a major factor in this game, and Ole Miss needs to contain that.

For Louisville, everything in their offense needs to run through Brown and control the clock. Brown averages just 11.2 carries per game last year, which is not going to be enough to control the clock against Ole Miss. While Isaac Brown needs to be the focus, Keyjuan Brown also needs to be mixed in. He has for 100 or more yards in each of his last three games last year, and while not the same big-play threat, is great at picking up short yardage and keeping the chains moving.

On defense, they have to limit the big plays of Ole Miss. Last year, the secondary allowed just six yards per pass, which was eighth in FBS. They were also 26th in yards per rush, allowing just 3.6 yards per rush. Last season, Ole Miss led the nation in total offensive snaps, was third in yards per game, eighth in yards per play, 11th in scoring, and was top ten in the nation in explosive plays. If Louisville is going to have a shot in this game, they have to limit the big plays and force Ole Miss to convert third downs, which they did just 42 percent of the time last year.

Ole Miss vs. Louisville Prediction and Pick

This is a high-profile Week 1 matchup between two teams that have playoff aspirations. The Cardinals will come in fired up, scheduling this game after Georgia backed out of their series with Louisville. Meanwhile, Trinidad Chambliss and Kewan Lacy look to get their Heisman campaigns off to a solid start. If Ole Miss can get an early lead, that could take the ground game out of the question for Louisville. Forcing Kienholz to consistently throw will lead to an Ole Miss win here.

Final Ole Miss vs. Louisville Prediction and Pick: Ole Miss -6.5 (-118) and Under 55.5 (-115) 

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