The Louisville Cardinals take on the Ole Miss Rebels in Nashville, Tennessee, on Sunday, Sept. 6. Kickoff is set for 7:30 p.m. ET on ABC.
Ole Miss is favored by -6.5 points on the spread with a moneyline of -265. The total is set at 54.5 points.
Here’s my Louisville vs. Ole Miss predictios and college football picks for Sunday, September 6.
Louisville vs Ole Miss Prediction
- Louisville vs. Ole Miss Pick: Ole Miss -7 or Better
My Ole Miss vs. Louisville best bet is on the Rebels to cover the spread. Find the best line available on our live NCAAF odds page.
Louisville vs Ole Miss Odds
| Louisville Odds | ||
|---|---|---|
| Spread | Total | Moneyline |
+6.5 +100 | 54.5 -115o / -105u | +215 |
| Ole Miss Odds | ||
|---|---|---|
| Spread | Total | Moneyline |
-6.5 -122 | 54.5 -115o / -105u | -260 |
- Louisville vs Ole Miss point spread: Ole Miss -6.5 (+100), Louisville +6.5 (-122)
- Louisville vs Ole Miss over/under: 54.5 (-115o / -105u)
- Louisville vs Ole Miss moneyline: Louisville +215, Ole Miss -260
Louisville vs Ole Miss Preview
Louisville Cardinals Betting Preview: How Will QB Perform?
The big unknown coming into the season for Louisville is the dual-threat capability of a new transfer quarterback. Lincoln Kienholz enters the 2026 season as the Cardinals' signal caller after transferring from Ohio State. He has a career 36 passing attempts dating back to 2023.
Head coach Jeff Brohm will limit downfield action for his new quarterback, but he will allow the senior to flash his mobility with scrambles and plenty of throws while on the move.
Both the head coach and offensive coordinator Brian Brohm have emphasized that the Louisville offense has an expanded playbook this season thanks to Kienholz.
The Louisville defense will continue to field one of the best nationally in various categories. The Cardinals ended 2025 top-15 in defensive success rate, limiting explosives and third nationally in pass rush grading, per PFF.
A number of havoc makers return to the defense, including edge Clev Lubin, corner Tayon Holloway and safety Koen Entringer.
Ole Miss Rebels Betting Preview: Chambliss for Heisman?
Head coach Pete Golding will look to ride the 2025 momentum of a national semifinal game into the 2026 season.
That task became easier with eligibility concerns being relieved for quarterback Trinidad Chambliss. The former Ferris State quarterback has Heisman aspirations after a 22-touchdown season that saw 29 big-time throws to just 13 turnover-worthy plays.
The return of Kewan Lacy makes the Rebels' backfield one of the most explosive in the country.
Golding will field another stingy defense after finishing top-25 in opponent finishing drives a season ago. Edge Suntarine Perkins returns after leading the team with 65 pressures. Linebacker Keaton Thomas joins from Baylor after recording 80 tackles last season.
Defensive interior Will Echoles returns to the trench after grading as the best run defender of any Rebels defender in 2025.
The biggest question heading into the Louisville game is the Rebels' ability to tackle in space, as they finished last year at 77th in PFF tackle grading.
Louisville vs Ole Miss Pick, Betting Analysis
There are more questions with Louisville than Ole Miss heading into this Week 1 showdown. The Cardinals will use a dual-threat RPO game dependent on Kienholz's legs, a factor that has not been seen before or used by Brohm's playbook.
Running back Isaac Brown is healthy after starting camp with hamstring issues. He's averaging 4.5 yards after first contact in 263 career rushing attempts. The Louisville offense must produce on the ground, as four of its top five pass catchers from a season ago have moved on.
The Ole Miss defense will be prepared to take on the rush attack of Kienholz and Brown, as it returns four of its top five tacklers. Echoles and Perkins led a defense that ended 2025 ranked 36th in broken tackles allowed, a signal that Brown could have a limit on explosive plays.
Thomas ranked as one of the highest Big 12 defensive players in run defense and tackle grading, and is now roaming between the tackles for the Rebels' defense. Louisville needed the elusiveness of Brown a season ago, as the offensive line ranked poorly in line yards and bottom-15 in stuff rate.
The Action Network projects Ole Miss as more than a touchdown favorite, well ahead of the market number that has dipped in favor of Louisville. Chambliss and Lacy are expected to be as potent as the 2025 version, a known factor in comparison to the new Louisville offense.
With Brohm adding an expanded playbook with a quarterback that has limited experience, look to back the Rebels at a touchdown or less.
Pick: Ole Miss -7 or Better
