USC vs Illinois Predictions, Picks & Spread for Big Noon Kickoff

• Illinois looks to bounce back from a 53-point loss.
• Can USC grab a cross-country win?
• I’ve provided my USC vs Illinois predictions and pick below, along with the betting lines.

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Week 5 of the college football season rolls on with a first-time Big Ten matchup between the USC Trojans and Illinois Fighting Illini. No.21 USC (4-0) and No.23 Illinois (3-1) are looking to strengthen their College Football Playoff cases. Illinois plays host at noon ET on Saturday, September 27th, on a FOX broadcast.

Read below for my USC vs Illinois prediction for Saturday, in addition to the updated betting lines.

USC vs Illinois Predictions & Pick

• USC -6.5 (-114, FanDuel)

USC has rocketed into the polls after a blistering start. They blew out Missouri State and Georgia Southern by 60 and 39, respectively, to open the season. They opened their Big Ten slate with a pair of multi-score wins over Purdue and Michigan State.

The man of the hour is quarterback Jayden Maiava. He leads the Big Ten in passing, averaging a ludicrous 12.7 yards per attempt (leading the country by over a yard per attempt). The USC signal caller has 13 total touchdowns with zero interceptions, fueling the Trojans to 52.5 points per game thus far. Maiava had five total touchdowns last week in USC’s late-night win over Michigan State.

Only one DI (FBS/FCS) player in the last 30 years has recorded at least 1200 passing yards, 4 rushing TD, a 70.0 completion percentage & 0 interceptions through 4 team games of a season:

USC’s Jayden Maiava (2025)

That’s it. pic.twitter.com/fvcP6HMPot

— Greg Harvey (@BetweenTheNums) September 25, 2025

Maiava has no shortage of weapons at his disposal. USC’s rushing attack is averaging a whopping 7.1 yards per carry, including Waymond Jordan’s robust 7.8 yards per carry on 57 rushes so far.

USC has one of the best receiver duos in the country in Makai Lemon and Ja’Kobi Lane. Lemon leads the conference with 24 catches and 438 yards. Lane leads the conference averaging 26.6 yards per catch. Both receivers are likely top-60 picks in the NFL Draft.

USC has had a havoc-creating defense to this point. Eric Gentry leads the country with 27 solo tackles, and he leads the Big Ten with seven tackles for loss. On the back end, safety Bishop Fitzgerald leads the conference in interceptions. He and Jamaal Jarrett each have a pick-six to their names.

JAMAAL JARRETT RUMBLIN' AND STUMBLIN' ALL THE WAY TO THE END ZONE @uscfb pic.twitter.com/S5SUcKMbRp

— CBS Sports College Football 🏈 (@CBSSportsCFB) September 14, 2025

Illinois got off to an explosive start behind fifth-year quarterback Luke Altmeyer. They won by 49, 26, and 38 before heading to Bloomington for a good, old-fashioned beatdown. No.9 Illinois left Indiana with a 63-10 loss, dropping them 14 spots in the polls.

Altmeyer has had a strong opening to the season, posting 10 total touchdowns and zero interceptions through four games. He’s completing 70% of his passes and encouraging a breakout from senior receiver Hank Beatty. Beatty leads the team with 21 catches for 302 yards, and he even tacked on a 25-yard rushing touchdown.

Kaden Feagin has fueled the running back room with 240 yards and three touchdowns to this point. Ca’Lil Valentine and Aidan Laughery have been nice change-of-pace backs, contributing over 100 yards and multiple touchdowns each.

The strength of the Illinois team had been the secondary before cornerback Xavier Scott went down with an injury in Week 3. Without Scott, the dam broke last week. Safety Matthew Bailey will be asked to anchor the back end while Gabe Jacas generates pressure up front.

I asked Bret Bielema for the latest on Xavier Scott:

"Sometimes the most difficult moment lead to bigger and better blessings."

-Successful surgery, will be on the sidelines this Saturday for USC game

-"Return date would be at the end of the year, we're going to have to play… pic.twitter.com/lGtoaApJrx

— Glenn Kinley (@glenn_kinley) September 25, 2025

Facing a depleted secondary, I expect USC to be able to throw the rock and put up points. Maiava is as long as +1700 to win the Heisman (BetRivers), so place your bets now before a statement win over a ranked Illinois team.

USC vs Illinois Betting Lines

The oddsmakers have listed USC as a road favorite with a total between 60.5 and 61.5. Over bettors can get -115 odds on over 60.5 at FanDuel. Under bettors can get -122 odds on under 61.5 at DraftKings.

USC bettors can get the Trojans at -6.5 on the spread at FanDuel (-114 odds) or -245 on the moneyline, also from FanDuel. Illinois bettors can get the Illini on the spread at +7 on Caesars (-115 odds) or +205 on the moneyline, also from Caesars.

Odds as of Sept. 26, 2025 at 10 PM ET. Browse our top sports betting apps before wagering on USC vs Illinois.

USC vs Illinois Previous Matchups

USC and Illinois will play their first Big Ten matchup this week. It is their first matchup generally since the 2008 Rose Bowl. In that game, the Pete Carroll-coached Trojans set the then-Rose Bowl scoring record with a 49-point outburst to clobber the Illini.

The last time USC played Illinois Pete Carroll led this team out into the Rose Bowl game, Jan 1st 2008 and won 49-17. ✌️

The crowd cheered Pete out the tunnel. Kirk Herbstreit @KirkHerbstreit wanted to pick Pete’s brain about the game and Lee Corso was taking pics.

Fight On!✌️ pic.twitter.com/TTLK1DMKsC

— Trojan Football ✌️ ᶠᵃⁿ (@TrojanFBx) September 26, 2025

USC holds an 11-2 lifetime advantage, including an undefeated record in Illinois. Illinois’ only wins are a 19-0 win back in 1935 and a 14-13 win in 1989. Future No.1 overall pick Jeff George quarterbacked Illinois in their most previous win over USC.