If you’d been told back in the summer that, come November, only one of Clemson or Louisville would still be in the ACC title hunt, few would have predicted it would be the Cardinals.
Yet that’s where things stand as the Tigers’ turbulent season rolls on with a trip to Kentucky on Friday, November 14. And with two conference losses already, the Cardinals can’t afford another misstep.
However, the Tigers would love nothing more than to put an end to the Cardinals' ACC title hopes, and my Clemson vs. Louisville predictions and college football picks explain how.
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Clemson vs Louisville prediction
Clemson vs Louisville best bet: Clemson moneyline (+120)
The Louisville Cardinals need a bunch of things to go their way if they want to reach the ACC Championship, starting with beating the Clemson Tigers on Friday night.
The thing is, Jeff Brohm has had problems with this kind of game. Not Clemson specifically — the Cardinals went into Death Valley and upset the Tigers last season — but just winning games he’s supposed to. Just look at last week’s game against Cal, for example.
And while it’s not a wide margin, the Cardinals are favored. This is a big deal considering Louisville hasn’t been the favorite in this matchup since 2016, and that was just as one-point chalk.
It shows how rough Clemson's season has been. The Tigers entered the year with national title aspirations. However, an underperforming defense, a one-dimensional offense, and injuries have led to a shocking 4-5 record.
That said, the Tigers are still fighting for bowl eligibility and are coming off a 24-10 win over Florida State. QB Cade Klubnik was stellar in that win, going 20-for-27 with 221 yards, a touchdown, and no picks.
Conversely, Miller Moss has been one of Louisville's problems, averaging just 6.9 yards per attempt and has an 11-7 touchdown-to-interception ratio. Meanwhile, star running back Isaac Brown will miss his second straight game.
While I called Clemson’s defense disappointing, it still ranks 32nd in success rate. Louisville is 16th. This should be a close game, and the Tigers will have the better QB play with Klubnik. So, I like Clemson to pull off the upset at the end of the night.
Clemson vs Louisville same-game parlay
Overall, the touchdown numbers haven’t been there for Klubnik, but at plus money, it’s worth adding Over 1.5 TD passes. He hasn’t been flashy, but he’s still tossed multiple TDs in three of his last five games. And Louisville is coming off a game where Jaron-Keawe Sagapolutele threw for 323 yards and two scores.
Meanwhile, with Brown out, it should mean a big workload for backup Keyjuan Brown. Brown has been in a groove lately, having carried the ball at least 10 times for 94 yards in each of his last three games. You can run on Clemson, which ranks 67th in EPA per rush.
Clemson vs Louisville SGP
- Clemson moneyline
- Cade Klubnik Over 1.5 TD passes
- Keyjuan Brown Over 79.5 rushing yards
Our deep-ball SGP: Join the Klub
With no Bryant Wesco, a now-healthy Antonio Williams is clearly Klubnik's top target. He has 29 receptions for 343 yards over his last four games and has scored in back-to-back games.
Clemson vs Louisville SGP
- Clemson moneyline
- Cade Klubnik Over 1.5 TD passes
- Keyjuan Brown Over 79.5 rushing yards
- Antonio Williams anytime touchdown
Clemson vs Louisville game predictions
Clemson vs Louisville moneyline prediction
Clemson isn't your typical 4-5 team. It's talented and fighting for bowl eligibility, with the better QB in Klubnik. With no Brown for Louisville, I like the Tigers to win.
Clemson vs Louisville spread prediction
Since I’m taking Clemson on the moneyline, covering the spread is straightforward. Both teams have struggled to cover spreads this season, but the Tigers have at least gone 3-2 ATS in their last five games overall.
Clemson vs Louisville Over/Under prediction
I would lean toward the Under here. This is a matchup of two underwhelming offenses going against strong defenses. Klubnik is solid, but the Tigers can’t run and struggle in the red zone, while Cardinals QB Moss has struggled, and Brown is out.
Clemson vs Louisville odds
- Spread: Clemson +2.5 | Louisville -2.5
- Moneyline: Clemson +120 | Louisville -142
- Over/Under: Over 51.5 | Under 51.5
Clemson vs Louisville trend to know
Louisville has only covered the Spread in 1 of its last 7 games at home for -5.60 Units and a -73% ROI. Find more college football betting trends for Clemson vs Louisville.
How to watch Clemson vs Louisville
| Location | L&N Federal Credit Union Stadium, Louisville, KY |
| Date | Friday, November 14, 2025 |
| Kickoff | 7:30 p.m. ET |
| TV | ESPN |
Clemson vs Louisville latest injuries
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Odds are correct at the time of publishing and are subject to change.
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