Louisville vs. Ole Miss Prediction, Odds and Key Players to Watch for College Football Week 1

In an opening week of the college football season that's loaded with lopsided matchups, there's one ranked vs. ranked game set to take place on Sunday when No. 24 Louisville takes on No. 9 Ole Miss at the Liberty Mutual Music City Kickoff in Nashville.

Louisville is looking to build off a strong 2025 season, while Ole Miss will be trying to keep its momentum in the post-Lane Kiffin era.

Let's dive into the odds and my best bet for this marquee game.

Louisville vs. Ole Miss Odds, Spread, and Total

Odds via Caesars Sportsbook

Spread

Louisville +6.5 (-103)
Ole Miss -6.5 (-118)

Moneyline

Louisville +215
Ole Miss -265

Total

OVER 55.5 (-106)
UNDER 55.5 (-114)

Louisville vs. Ole Miss How to Watch

Date: Sunday, September 6
Time: 7:30 p.m. ET
Venue: Nissan Stadium
How to Watch (TV): ABC
Louisville record: 0-0
Ole Miss Tech record: 0-0

Louisville vs. Ole Miss Betting Trends

Ole Miss won and covered the spread in its most recent game against Louisville in 2021
Louisville is 4-6 against the spread in its last 10 games
The UNDER is 6-4 in Louisville's last 10 games
Ole Miss is 5-5 against the spread in its last 10 games
The OVER is 5-5 in Ole Miss's last 10 games

Louisville vs. Ole Miss Key Player to Watch

Trinidad Chambliss, QB - Ole Miss Rebels

Trinidad Chambliss was likely to be one of the top quarterbacks taken in the 2026 NFL Draft, but Chambliss filed an appeal with the NCAA for another year of eligibility, and after it went to Mississippi state court, the appeal was approved. He's back for one more season after throwing for 3,937 yards, 22 touchdowns, and three interceptions while adding 527 rushing yards a year ago.

Louisville vs. Ole Miss Prediction and Best Bet

In my Week 1 upset picks article, I made the case for betting on Louisville to win this game outright:

Trinidad Chambliss is back for another year at Ole Miss, but that's not enough for me to think that the Rebels will be the dominant team they were last season under Lane Kiffin. There's no doubt that Ole Miss has plenty of offensive weapons, but so does Louisville. Isaac Brown, the Cardinals' running back, averaged a blistering 8.8 yards per carry last season. If he can replicate numbers even close to his 2025 production, Louisville is going to be a tough offense for any defense to stop.

Let's also remember how good this Louisville defense was last season, ranking 25th in the country in defensive success rate, compared to Ole Miss, which ranked 56th in that metric while ranking 86th in opponent rush success rate.

I have more faith in the team with the returning head coach. This could be a big season for Jeff Brohm.

Pick: Louisville +215 via Caesars

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