Oregon vs. USC Prediction, Odds and Key Players to Watch for College Football Week 4

A top-25 matchup in the Big Ten takes place in Week 4 of the college football season, as the No. 20 Oregon Ducks take on the No. 12 USC Trojans on Saturday night.

Dante Moore and the Ducks are coming off a feel-good win over Portland State last week, but they are just 2-1 this season after a shocking upset loss to Oklahoma State. Oregon may need to run the table in the Big Ten to lock up a playoff spot, and it’s actually set as a favorite on the road in this matchup.

Meanwhile, the Trojans are 4-0 (they played in Week 0) after a close call against Rutgers in Week 3. Jayden Maiava and Co. put up 42 points in that game, but the USC defense (35 points allowed) has given up over 25 points in three of four games this season.

This is the first matchup against a ranked opponent for both teams, and USC enters it with a shaky 1-3 against the spread record despite being 4-0.

With two star quarterbacks – and potential NFL prospects – facing off, how should we bet on this matchup?

Here’s a look at the odds, a player to watch and my prediction for this Big Ten clash on Sept. 26.

Oregon vs. USC Odds, Spread and Total

Odds via DraftKings Sportsbook

Spread

Oregon -3 (-108)
USC +3 (-112)

Moneyline

Oregon: -162
USC: +136

Total

62.5 (Over -108/Under -112)

Oregon vs. USC How to Watch

Date: Saturday, Sept. 26
Time: 7:30 p.m. EST
Venue: Los Angeles Memorial Coliseum
How to Watch (TV): NBC
Oregon record: 2-1
USC record: 4-0

Oregon vs. USC Key Player to Watch

Dante Moore, Quarterback, Oregon

Moore had an ideal bounce-back game in Week 3, throwing for 280 yards and four scores in an 84-0 win over Portland State.

After a rough start to 2026, the Ducks finally are trending in the right direction on the offensive end heading into this marquee matchup with USC.

Moore had thrown for nine scores in three games, completing over 68 percent of his passes. However, Oregon had not been able to put away Boise State or Oklahoma State in Weeks 1 and 2, failing to cover and losing one game outright.

If Moore wants any chance at getting back in the Heisman conversation, he needs to lead the Ducks on a major winning streak in Big Ten play.

Oregon vs. USC Prediction and Pick

USC’s close scare with Rutgers in Week 3 was concerning, and this defense has been far from good in the 2026 season.

USC allowed 26 points to San Jose State and 30 points to Louisiana earlier in the season, ranking 104th in the country in defensive success rate.

For all of the struggles that Oregon has dealt with in the first three weeks, the Ducks are ninth in EPA/Play on offense and 12th in EPA/Play on defense. A lot of that has to do with the blowout of Portland State, but I’m not completely out on the Ducks as a potential playoff contender.

Meanwhile, USC ranks outside the top 100 in EPA/Rush on defense and has not faced a quality team yet in the 2026 season.

I think this step up in class may be too much for the Trojans, and I think oddsmakers got it right with the Ducks as field-goal favorites.

Pick: Oregon -3 (-108 at DraftKings)

Odds refresh periodically and are subject to change.

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