Best College Football Upset Picks and Underdog Bets - Week 2 CFB Predictions (2025)

September 5, 2025

Brant's best college football predictions and upset picks for Week 2 of the 2025 season. His top CFB underdogs and favorites on upset watch, including Ole Miss, more.

If you missed my upset watch column last week, you were probably shocked when Florida State walked over Alabama start-to-finish in Tallahassee last weekend. Then again, if you did read my column last week, you were definitely underwhelmed with Northwestern’s showing in New Orleans. It turns out I was wrong on Preston Stone elevating the Wildcats' offense. Hitting on two of my picks straight up and a third against the spread, it wasn't the worst Week 1 ever.

You can’t win them all, especially when the criteria is picking a multitude of underdogs. With that being said, I have identified a few Week 2 matchups that you should have your eyes on this weekend.

Week 2 doesn’t have as many big-time games on the slate as Week 1 had, but there are a number of under-the-radar football games that real college football fans need to be tuned in for. Keep a close eye on these four games, as I think there is a good shot that these underdogs give their opponents a run for the money.

Duke Blue Devils (vs. No. 11 Illinois)

Duke got out to a slow start in its Thursday night opener against Elon, but Manny Diaz’s squad ended up pulling away with a 45-17 victory. Quarterback Darian Mensah, one of the highest-paid players in all of college football, was as advertised. The sophomore passed for 389 yards and three touchdowns, although he was against an FCS-level defense.

Darian Mensah's Duke debut:

😈 27/34
😈 389 YDS
😈 3 TD @DukeFootball pic.twitter.com/sXX54r54f3

— ACC Network (@accnetwork) August 29, 2025

Illinois rolled over Western Illinois 52-3 in its season opener. Luke Altmyer looked comfortable despite losing most of last year’s production at receiver, passing for 217 yards and three touchdowns. Again, this was against a low-level FCS defense, so take the numbers with a grain of salt.

Neither Duke nor Illinois played a team with a pulse in Week 1, making this week's matchup all the more intriguing for fans on both sides. This will be the first test for both teams, and on paper, this is a lot more evenly matched than the rankings or the spread indicate.

Home underdogs got the job done last week, as they often do, and I think having Duke listed as an underdog is disrespectful to the Blue Devils. Illinois is a good football team, but Duke is similar in a lot of facets and arguably has a more talented quarterback calling the shots offensively.

This will be a close, hard-fought game between two "fundamentals" coaches in Diaz and Bret Bielema. Both quarterbacks have talent, and both teams are well-disciplined. With the Illini talked up as a potential playoff team, I think Duke spoils their party this week in a massively underrated noon game.

Kentucky Wildcats (vs. No. 20 Ole Miss)

It happened last year on the road with what I believe was a worse Kentucky team and a better Ole Miss team. Yet, the spread here is still over 10 points despite Mark Stoops’ team itching for a signature win and opening its SEC season at home.

Last week’s win over Toledo wasn’t pretty, but the Wildcats are 1-0. Ole Miss won 63-7 over Georgia Southern, but Austin Simmons threw two interceptions. Simmons can’t afford to make mistakes in his SEC debut, and Stoops will be hunting ways to exploit the young quarterback in Lexington. His defense played well in the win over Toledo, and the Wildcats will need to play through their defense to have a shot at Lane Kiffin's squad on Saturday.

Zach Calzada’s 2021 highlight was taking down No. 1 Alabama 🔥

📌 285 yards

📌 3 TDs

📌 Now in the Transfer Portal

pic.twitter.com/jGJt28rcpd

— 247Sports (@247Sports) December 13, 2021

Zach Calzada, on the other hand, is 24 years old. He upset top-ranked Alabama when he was at Texas A&M in 2021, and is itching for another big-time SEC upset. This may be his best opportunity to do so this season. When in doubt, take the experienced quarterback at home in an early-season matchup.

Ohio Bobcats (vs. West Virginia)

Rich Rodriguez’s re-debut at West Virginia went well, as the Mountaineers rolled Robert Morris, 45-3. This week, they travel to MAC country to take on the Ohio Bobcats. The Big 12 squad is only favored by three points despite taking on an opponent from a lesser conference.

Ohio, on the other hand, came very close to pulling off an upset over Rutgers on the road in Week 1. Quarterback Parker Navarro, arguably the best signal-caller in the MAC, threw for 239 yards and three touchdowns while rushing for 93 yards and another score. New head coach Brian Smith had no problem carving up defensive maestro Greg Schiano’s Scarlet Knights, and he and Navarro will have their way with the Mountaineers' defense in the Bobcats’ home opener.

This is the G5 over Power 4 matchup to keep your eyes on this weekend. With the door to the G5 playoff spot wide open after Boise State’s shocking Week 1 defeat, do not sleep on the Bobcats' chances to work their way into the conversation with a big win this weekend.

UConn Huskies (at Syracuse)

It has been a long, long time since UConn had a respectable football team. Historically, they are one of the worst D-I programs, and the program nearly went under a few seasons ago.

Jim Mora has the Huskies on the right trajectory. He led them to a 9-4 record last season, their first winning season since 2010. A lot of the pieces from that team are back this year, and they dominated Central Connecticut 59-13 in the season opener behind the arm of seventh-year quarterback Joe Fagano.

This weekend's matchup with Syracuse is one of the toughest games on the schedule. The Orange did not look great last weekend in a dominant loss to Tennessee, and while UConn is a major step down in competition, it is possible that they are being overlooked.

Fran Brown's team is only favored by 6.5 points, and with the experience and continuity that Jim Mora has on his squad, the Orange should be placed on upset alert this weekend.

Michigan Wolverines (at No. 18 Oklahoma)

Going on the road with a freshman quarterback making his second career start, and first in a big-time game, is not an easy feat. Oklahoma’s John Mateer looked solid in Week 1, passing for 392 yards and three touchdowns in a 35-3 win over Illinois State. This will be one of the most hyped home games in a long time for Sooners fans, and it will undoubtedly be a hostile environment at night in Norman.

With that being said, the Wolverines are still a physical football team. While Bryce Underwood is young, he flashed elite upside in the Week 1 win over New Mexico. Michigan’s run game is once again elite with Alabama transfer Justice Haynes leading the way, and Underwood's talent elevates the offense's ceiling infinitely from where it was last season with Davis Warren and Alex Orji.

Bryce Underwood debut highlights 🔥 pic.twitter.com/m3FJAS5NEH

— JD 〽️ (@MGoJDBlue) August 31, 2025

Sherrone Moore will be on the sidelines for Michigan after conveniently not being suspended for their biggest game in the first quarter of the season. On the opposing sideline, Brent Venables will be hunting for a signature win to get himself off the hot seat that Sooners' fans have placed him on.

The hostile environment mixed with Oklahoma winning the experience battle makes this 5-point spread reasonable. However, the Wolverines’ dominance at the line of scrimmage is my key to the game, and I think they have what it takes to pull off the major road win despite star linebacker Jaishawn Barham missing the first half after a targeting call last weekend. Wolverines over Sooners in Norman, cementing the Big Ten's status as the top conference in college football.

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