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As we head into Week 4 of the 2025 college football season, we've already seen some massive upsets. Florida State took down Alabama in Week 1, South Florida knocked off both Florida and Boise State and, last week, Texas A&M went into South Bend and beat Notre Dame. Are there any more upsets in store for Week 4? 

If you're interested in college football betting on underdogs, we've got you covered. As we do every week, we're highlighting five underdogs who we feel can knock off a favored opponent. Two of our picks are part of ranked vs. ranked conference battles. 

All spreads and money line odds are courtesy of DraftKings Sportsbook, where new users get $200 in bonus bets instantly and over $200 off NFL Sunday Ticket. Click here to sign up for DraftKings:

Syracuse (+17.5, +550) at Clemson

Boy it's been a tough start to 2025 for Clemson, huh? After making the College Football Playoff last year and pushing Texas in the first round, the Tigers entered 2025 with big aspirations, especially with the return of quarterback Cade Klubnik, who passed for 36 touchdowns in 2024. So far not so good for Klubnik and Co. as the Tigers are 1-2 entering this matchup with Syracuse after falling to LSU in Week 1 and losing at Georgia Tech last week. 

Yes, LSU is one of the better teams in the country right now, and yes, Georgia Tech looks pretty dang good so far, but sandwiched between those losses was an ugly Clemson win over Troy. Dabo Swinney's club just does not look good so far. The Orange, meanwhile, are 2-1 and have been able to score quite a bit, even scoring 26 against Tennessee in Week 1. This spread and the money line odds seem too wide, even with Clemson at home. The Orange can absolutely push the Tigers in this game.

Auburn (+6.5, +205) at Oklahoma

We've got a revenge game of sorts as Auburn quarterback Jackson Arnold faces his old team, Oklahoma, in SEC action. The Sooners let Arnold walk via the transfer portal to make way for John Mateer, who followed his offensive coordinator Ben Arbuckle from Washington State to Oklahoma. 

The transfers have worked out well for everyone so far as both sides are undefeated, Mateer is a Heisman candidate and Arnold is completing nearly 70% of his passes and has eight total touchdowns so far. Both teams look impressive so far and are looking for big SEC statement wins, but Mateer has been more turnover-prone than Arnold, which could skew things Auburn's way. 

Tulane (+10.5, +300) at Ole Miss

Ole Miss survived not one, but two SEC clashes over the last two weeks, beating Kentucky 30-23 and Arkansas 41-35. For a team that made a stink about missing the College Football Playoff a year ago, Lane Kiffin's squad is in the midst of a highwire act against lesser competition so far this year. Enter Tulane.

The Green Wave are 3-0 after wins over Northwester, Southern Alabama and Duke to open the year. Tulane also enters this contest in a great spot as Ole Miss could be looking ahead to next weekend, when the Rebels host LSU, which is currently ranked No. 3 in the nation. Kiffin's squad hasn't done as well as expected over lesser opponents the last two weeks, and if the Rebels continue to act that way, they'll get tripped up sooner than later. 

Illinois (+5.5, +180) at Indiana

Two undefeated and highly-ranked Big Ten rivals square off in maybe the biggest matchup this rivalry has seen to date. Illinois is ranked No. 9 in the nation while Indiana, which made the College Football Playoff last years, is No. 19. There's an argument the two best quarterbacks in the conference are squaring off in Bloomington on Saturday as Illinois' Luke Altmyer has 709 passing yards and eight touchdowns to no interceptions on 71.8% completions this year whole Indiana's Fernando Mendoza, a Cal transfer, has 708 passing yards and nine touchdowns to no interceptions with a 72.4% completion rate this year.

The Illini had their best mark under Bret Bielema last year with a 10-3 record, and they appear primed for another big step forward. They could be, ironically enough, this year's Indiana out of the Big Ten as the Hoosiers went 11-1 and made the College Football Playoff last year. Indiana had to revamp its roster after losing some key players from that CFP team, with Mendoza the headliner. Illinois has a stellar defense and, in all likelihood, the better top-to-bottom roster in this matchup, so the Illini have a great chance to pull off a statement win on the road. 

South Carolina (+10, +285) at Missouri

Keep an eye on the odds and line moving with this one as South Carolina deals with an injury to quarterback LaNorris Sellers. Sellers, a dynamic dual-threat quarterback, is off to a slower start this year after a stellar 2024 camapign, but he left Saturday's 31-7 loss to a now-ranked Vanderbilt squad due to a concussion. Sellers is questionable for this SEC tilt against an undefeated Missouri squad.

The Tigers handled Central Arkansas and Louisiana and also beat rival Kansas 42-31, pulling away late over the less-talented side. The Gamecocks lost to the Commodores last week but previously defeated South Carolina State and Virginia Tech. 

If Sellers plays, the dynamic changes quite a bit here. Even though he's been less than stellar in 2025, Sellers is an incredibly talented player who can take games over with his arm or legs, as we saw late last year. But if Sellers is out, this will be a tougher task as his backup, Luke Doty, completed 18 of his 27 attempts for just 148 yards and a pick against Vanderbilt last week while losing a fumble. Missouri is too talented to fall to a Doty-led attack, but the Tigers will have their hands full if Sellers suits up.