Syracuse vs. Clemson Prediction, Odds and Key Players to Watch for College Football Week 4

Betting odds, pick and prediction for the Syracuse vs. Clemson battle in Week 4.

The Clemson Tigers and quarterback Cade Klubnik have not covered the spread yet in 2025. / Brett Davis-Imagn Images

The Syracuse Orange are 2-1 so far in the 2025 season, but they lost their only matchup with a ranked opponent – Tennessee – in Week 1.

They were expecting to face a ranked opponent in Week 4, but losses to LSU and Georgia Tech have knocked the Clemson Tigers out of the top-25 entirely. Clemson is facing an uphill battle to get back to the College Football Playoff, and Dabo Swinney’s bunch needs a win at home in Week 4 more than anything.

Oddsmakers have set Clemson as a 17.5-point favorite in Week 4, but can bettors really lay the points with a team that is 0-3 against the spread and struggling to score the ball in 2025?

Let’s dive into the odds, my prediction and more for this ACC matchup in Week 4. 

Syracuse vs. Clemson Odds, Spread and Total

Odds via DraftKings Sportsbook

Spread

• Syracuse +17.5 (-112)
• Clemson -17.5 (-108)

Moneyline

• Syracuse: +550
• Clemson: -800

Total

• 55.5 (Over -108/Under -112)

Syracuse vs. Clemson How to Watch

• Date: Saturday, Sept. 20
• Time: 12:00 p.m. EST
• Venue: Memorial Stadium
• How to Watch (TV): ESPN
• Syracuse record: 2-1
• Clemson record: 1-2

Syracuse vs. Clemson Key Player to Watch

Cade Klubnik, Quarterback, Clemson

A Heisman hopeful entering the 2025 season, Klubnik has all but killed his case in three weeks. Not only have the Tigers lost to LSU and to Georgia Tech, but the potential NFL draft pick has not played well in any game.

So far this season, Klubnik has completed just 59.1 percent of his passes for 633 yards, three touchdowns and three picks. On the ground, he has carried the ball 30 times for 59 yards and one score.

Things are going to have to turn around quick if Klubnik wants a chance to get drafted, and he has a chance to do so as a massive home favorite against Syracuse. 

Syracuse vs. Clemson Prediction and Pick

I’m not going to back the Tigers at this number given their poor start to the 2025 season, but I do think there is some value in the total on Saturday afternoon.

Clemson has scored just 10, 27 and 21 points this season, losing both games against Power Four opponents. While Syracuse is far from a powerhouse from a football standpoint, I wouldn’t be shocked if it gives this struggling Tigers team some issues.

Clemson’s defense is allowing just 338.3 yards per game, but the offense has been stuck in mud with Klubnik throwing as many interceptions (three) as he has touchdowns in the 2025 season.

Syracuse has put up at least 26 points in every game, but it did struggle a bit with both Tennessee and UConn in Weeks 1 and 2. 

I could see this game falling well short of this total at 55.5, especially if the Clemson offense sputters like it did early in Week 2 against Troy before coming back to win. 

Pick: UNDER 55.5 (-112 at DraftKings)

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Odds refresh periodically and are subject to change.

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