NFL Upset Predictions and Picks for Week 2 (Will Jacksonville Pull Off the Upset in Cincinnati?)

Iain MacMillan | Sep 11, 2025

The Jaguars are underdogs against the Bengals in NFL Week 2. / Lawrence: Courtney Culbreath/Getty Images, Burrow: Alika Jenner/Getty Images

NFL upsets were few and far between in Week 1. The Los Angeles Chargers beating the Kansas City Chiefs on Friday night, the Las Vegas Raiders taking down the New England Patriots, and the Bills winning as slight underdogs on Sunday Night Football were the only upsets in the opening week.

Don't expect that trend to continue. The NFL season brings chaos, and we're sure to see more as the season progresses, and maybe we'll see a handful of them in Week 2.

Matt Verderame, Iain MacMillan, and Peter Dewey are back this week to give their best upset pick for this week's slate of games.

• Matt Verderame, NFL Staff Writer
• Iain MacMillan, Senior Editor, Betting
• Peter Dewey, Associate Managing Editor, Betting

Matt Verderame Week 2 Upset Pick

Colts (+114) vs. Broncos (via DraftKings)

The Colts looked about as good as any team can in Week 1. Daniel Jones accounted for three touchdowns, and the defense, under new coordinator Lou Anarumo, pitched a shutout deep into the fourth quarter of a 33–8 blowout.

Yes, the Colts beat the hapless Dolphins, but Indianapolis has reason to believe that if Jones can continue being efficient. Of course, that won’t be easy against a Broncos defense that sacked Cam Ward six times in his NFL debut while not allowing a touchdown, but Denver’s offense also struggled mightily. 

Against the Titans, Bo Nix threw a pair of interceptions and lost a fumble while averaging 4.4 yards per attempt. The Colts figure to challenge Denver’s attack a bit more than Tennessee, and with the game being away from the Rocky Mountains, that might be enough to pull off the minor upset. 

Peter Dewey Week 2 Upset Pick

Jaguars (+142) vs. Bengals (via DraftKings)

Zac Taylor’s Cincinnati Bengals may have escaped with a win in Week 1, but their slow starts are still a thing. Cincy mustered just seven yards of offense in the second half of Week 1 against the Cleveland Browns, and it’s going to face a much tougher opponent in Week 2 in Jacksonville.

The Jaguars ran all over the Carolina Panthers in Week 1, and Liam Coen’s offense should be able to take advantage of a Cincy defense that was one of the worst in the NFL in 2024. I’m not sold on the Bengals having a solid defensive team despite slowing down the Joe Flacco-led Browns in Week 1. 

Ultimately, there is a major trend to watch on the Cincy side, as Taylor’s teams are just 2-11 straight up in Weeks 1 and 2 since he took over as Cincy’s head coach. After a strong showing in Week 1, I think the Jags are in a great spot to move to 2-0 on Sunday.

Iain MacMillan Week 2 Upset Pick

I rushed to bet the Falcons in this spot. Atlanta fell short to the Buccaneers, but Michael Penix Jr. looked every bit of a great NFL quarterback, and their defense looked much improved under Jeff Ulbrich. They could cause more problems for J.J. McCarthy than some people may expect.

Making McCarthy this big of a favorite in his second-ever NFL start seems like a stretch. Atlanta has the weapons to not only cover the spread against Minnesota but also win this game outright. The Falcons are my upset pick of the week.

Falcons +165 vs. Vikings (Via BetMGM)

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