#24 Louisville vs. #9 Ole Miss Prediction, Spread, NCAAF Picks – Sunday, September 6

The 2026 college football season closes out Week 1 with one of the most anticipated matchups on the schedule as the #24 Louisville Cardinals take on the #9 Ole Miss Rebels in Nashville's Nissan Stadium.

Both teams enter the season with legitimate College Football Playoff aspirations. Ole Miss has the higher national ranking and one of the most exciting QBs in college football, but Louisville has an elite running game, a veteran coaching staff, and an exciting QB in its own right.

For tonight's 7:30 p.m. ET kickoff on ABC, Ole Miss enters the matchup as a 6.5-point favorite with the over/under sitting at 54.5 points on PrizePicks.

Below, we’ll break down our Louisville vs. Ole Miss prediction and picks for Sunday’s CFB game in Week 1, including the spread for PrizePicks.

Make your Louisville vs. Ole Miss picks on PrizePicks now!

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#24 Louisville vs. #9 Ole Miss Prediction, Spread, Over/Under for Week 1

Ole Miss enters 2026 ranked #9 nationally after one of the best seasons in program history, where it went 13-2 and reached the College Football Playoff semifinals before falling to Miami 31-27.

QB Trinidad Chambliss is perhaps the biggest reason Ole Miss has legitimate championship expectations. The ex-DII transfer took over the starting job during the 2025 season and helped lead Ole Miss through the College Football Playoff, throwing for 3,021 yards and 21 TDs while adding 714 yards and 11 TDs with his legs.

The emergence of Chambliss has almost made people forget about RB Kewan Lacy, who also returns as one of the best running backs in the country. Lacy rushed for more than 1,700 yards and 24 TDs last season while averaging 6.5 yards per carry during Ole Miss' playoff run.

One cause for pause is that Ole Miss has undergone a coaching transition after head coach Lane Kiffin's departure, with former defensive coordinator Pete Golding taking over as head coach, while John David Baker takes over offensive play-calling duties.

Louisville, meanwhile, has plenty of reasons to believe it can compete. The Cardinals are coming off a quality 9-4 season capped by a 27-22 win over Toledo in the Boca Raton Bowl.

HC Jeff Brohm has transformed the Cardinals into one of the most consistent programs in the ACC, winning at least nine games in each of the last three seasons.

The Cardinals' biggest weapon is RB Isaac Brown, who led the nation in yards per carry last season at an absurd 8.8 yards per attempt. Fellow RB KeyJuan Brown was no slouch in his own right, proven by 7.3 yards per carry (third nationally).

At QB, the Cardinals will be trotting out Lincoln Kienholz, who takes over after transferring from Ohio State, where he competed for the starting job with QB Julian Sayin. Kienholz brings plenty of athleticism to Brohm's offense and should allow Louisville to run more designed quarterback runs and option concepts than in previous seasons.

Louisville vs. Ole Miss Spread, Over/Under for Week 1 – Sunday, September 6

Ole Miss enters Sunday’s game as a 6.5-point favorite against Louisville via PrizePicks.

Here are the full payouts for Louisville vs. Ole Miss on PrizePicks.

Make your Louisville vs. Ole Miss prediction on the spread on PrizePicks.

Team Picks data is live at the time of writing and is subject to change.

Louisville vs. Ole Miss Prediction on Spread for Week 1 – 9/6/26

Here are the key stats and trends behind our Louisville vs. Ole Miss prediction on the spread for Sunday, September 6.

• Brohm is 26-15-1 against the spread (ATS) as an underdog dating back to his time at Purdue, a 63.4% cover rate.
• This is a sneaky great matchup for the Cardinals, who will look to establish their lethal 1-2 ground game against an Ole Miss defense that ranked 82nd nationally in EPA/rush (.10) last season, per Game On Paper.
• Louisville will likely look to run both RBs and its new mobile QB to extend drives and keep the explosive Ole Miss offense on the sidelines.
• Defensively, the Cardinals could also cause problems for Chambliss, ranking 19th nationally in EPA/pass (-0.09).
• Louisville is no stranger to fast starts; it is 10-1 straight up in September under HC Jeff Brohm, who has gone a perfect 3-0 in season openers in his time with the Cardinals.

Lock in your Louisville vs. Ole Miss prediction on PrizePicks before Sunday’s CFB game.

Louisville vs. Ole Miss Picks, Player Stats for PrizePicks – 9/6/26

Here are the top Louisville vs. Ole Miss picks to target on PrizePicks for Sunday, September 6. Today’s CFB picks for PrizePicks include Isaac Brown and Kewan Lacy.

Louisville RB Isaac Brown vs. Ole Miss: 71.5 Rush Yards

• Isaac Brown is one of the most talented RBs in the country who plays in an offense that is expected to be quite run-heavy this year.
• Ole Miss’ defense ranked 39th nationally in EPA/pass but 82nd nationally in EPA/rush a season ago, creating a straightforward game plan for the Cardinals offense to run the ball early and often.
• All the incentives also line up well for Brown here. The Cardinals need to control the clock, attempt to keep Chambliss off the field, and make their new starting QB's first start as simple as possible. How do you accomplish those tasks? By running the football.
• Brown cleared this projection in six of the nine games he played in last season, as well as each of his last four games.
• After averaging 8.8 YPC in 2025, if Brown can even sniff that number this year, it could take less than 10 carries for him to reach this mark, a workload he seems likely to surpass tonight.

Add Isaac Brown to your PrizePicks lineup now.

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Ole Miss RB Kewan Lacy vs. Louisville: 88.5 Rush Yards

• Kewan Lacy averaged 114.0 rush yards per game last season.
• The Cardinals' defense was much better against the pass in 2025, ranking 19th nationally in EPA/pass (-0.09) but 55th in EPA/rush (0.05).
• Unlike Brown, who splits his work offensively, Lacy is the unquestioned lead back in this offense, often seeing carries in the mid-to-upper 20s last season.
• He cleared this projection in four of his last five games in 2025, including against Miami, when he played injured and still put up 105 yards on just 11 carries (9.5 yards per attempt).
• As 6.5-point favorites, the projected game script is favorable for Ole Miss owning a lead and perhaps leaning its pass/run splits towards the latter.

Add Kewan Lacy to your PrizePicks lineup now.

Make Louisville vs. Ole Miss Picks on PrizePicks

College football Week 1 wraps up with an absolute banger of a game this Sunday night in Nashville. The Rebels will look to replicate their tremendous 2025 season, while the Cardinals will look to play spoiler and prove they are ready to be a title contender this year.

Don't wait until kickoff — make your Louisville vs. Ole Miss pick on PrizePicks. There is a wide variety of player stat projections on the CFB board, so you can make predictions on yards, field goals, and more! Just pick your players, predict More or Less on their stats, and cash in on your predictions if you're right.

With Team Picks, you can make predictions on game winners, spreads, and over/unders — now available in 35 states.

Keep it here with the Playbook for continued CFB picks, predictions, futures, and more as we jump into 2026.