Ole Miss vs. Louisville prediction, picks, odds, spread: Rebels open season against upset-minded Cardinals

The only Week 1 game featuring two teams ranked in the preseason AP Top 25 pits No. 9 Ole Miss and No. 24 Louisville on Sunday night at Nissan Stadium in Nashville. It marks an immediate and massive test for two established programs with College Football aspirations but unforgiving schedules.

Louisville is a rare team with 11 Power Four opponents on its slate, and Ole Miss faces an unforgiving league grind during the SEC's first season with a nine-game conference schedule. Thus, the stakes will be high for a meeting between two teams with major offensive expectations.

Ole Miss coach Pete Golding retained star quarterback Trinidad Chambliss and standout running back Kewan Lacy amid the transition away from coach Lane Kiffin. Those two spearheaded the Rebels' charge to the semifinals of the College Football Playoff last season and have designs on making another deep postseason push.

Louisville finished 9-4 last season, but the Cardinals were left to wonder what could have been following a 7-1 start that included a road win over then-No. 2 Miami. November losses to Cal and Clemson by a combined four points wrecked the Cardinals' hopes of a truly special season and should serve as motivation entering 2026.

Ole Miss vs. Louisville: Need to know

The Kienholz factor: Louisville's expectations of an elite passing game didn't quite pan out like expected last year with USC transfer Miller Moss at quarterback. His production tapered off significantly in the season's second half, and Louisville's running game wasn't good enough to make up the difference. Fourth-year coach Jeff Brohm went back to the portal in 2026 to land ex-Ohio State backup Lincoln Kienholz. The former four-star prospect was edged by Julian Saying in a quarterback battle last year and is raring for his first starting opportunity as a redshirt junior. He's expected to bring an element of elusiveness to the Louisville offense that quarterbacks in Brohm's system don't always have. 

Brohm has the upset gene: In each of his three seasons at Louisville, the Cardinals have slayed a top-11 opponent. Last season, it was No. 2 Miami. In 2024, it was No. 11 Clemson, and in 2023, Louisville knocked off No. 10 Notre Dame. The trend goes back to Brohm's Purdue tenure, when the Boilermakers slayed a pair of top-5 opponents in 2021 (Iowa and Michigan State) after stunning No. 2 Ohio State in 2018. As a veteran coach who's had an entire offseason to implement a game plan for Ole Miss, expect to see some creativity from Brohm as the Cardinals try for another head-turning victory.

Establishing new targets: Ole Miss quarterback Trinidad Chambliss enters the season with legitimate Heisman Trophy aspirations after totaling nearly 4,500 yards from scrimmage last season. But he'll be throwing to a mostly new group of targets in 2026. Who will step up? Deuce Alexander is the leading returning target after reeling in 44 passes for 684 yards last season. After that, it will be on a group of transfers. Among them are Darrell Gill Jr. and Johnny Cook II (both from Syracuse), Isaiah Spencer (Virginia Tech) and Cameron Reed (Kentucky). Gill and Cook each surpassed 500 yards receiving within a weak Syracuse passing attack last season and should flourish within a better system. But whether the Rebels' passing attack can click immediately may determine how this Week 1 showdown pans out.

How to watch Ole Miss vs. Louisville live

Date: Sunday, Sept. 6 | Time: 7:30 p.m. ET Location: Nissan Stadium -- Nashville, Tennessee TV: ABC | Live stream: Fubo (Start watching, save $20!)

Ole Miss vs. Louisville prediction, picks

Ole Miss has a savvy veteran playmaker at quarterback who led the Rebels to key victories in major moments last season. Simply put, it's not smart to bet against someone like Trinidad Chambliss, even if the Rebels are breaking in new receivers and two new offensive tackles. Louisville's defense will be tested as they seek to contain Chambliss and star running back Kewan Lacy, and the Rebels should eventually be able to break the dam to build a two-possession lead. Pick: Ole Miss -7

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