The Buffalo Bills are hoping to get another good game from their new wide receiver. Meanwhile, the Lions face a tall task against Josh Allen. And here is the prediction for the Lions versus the Bills, with odds for Week 2 Thursday Night Football.

Both of these teams hold Super Bowl hopes for the 2026 season. And they each have questions they must answer if they want to live up to the hype.

NFL: Lions vs. Bills prediction, odds, pick for Week 2 of 2026

  • Lions: +5.5
  • Bills: -5.5
  • Over/Under: 55 points
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Lions vs. Bills Key Injuries

The Lions have ruled out linemen Christian Mahogany and Blake Miller, according to detroitlions.com. Also, cornerback DJ Reed is questionable.

“The Lions' injury report for “Thursday Night Football” is worrisome,” Tyler Sullivan and Jordan Dajanias wrote. “Starting right tackle Blake Miller (knee) and starting left guard Christian Mahogany (hip) have officially been ruled out. Plus, veteran defensive back D.J. Reed is questionable with a foot injury after being a limited participant in practice on Tuesday and Wednesday.”

It’s a potential problem for Lions QB Jared Goff, according to NFL.com.

“If Jared Goff’s timing and/or the blocking for Gibbs suffer as a result of the health issues on the front line, trying to keep up with Allen and Co. could quickly feel like an impossible task,” Dan Parr wrote.

As for the Bills, they’re in better shape. Safety Cole Bishop (knee/groin), running back Ty Johnson (hamstring), and defensive lineman TJ Sanders (knee/illness) managed limited practice on Wednesday.

The game could be a shootout.

“First one to 50 points wins?” Parr wrote. “The first game of Week 2 is loaded with offensive weaponry, featuring the current MVP favorite (Josh Allen) and the Offensive Player of the Year front-runner (Lions RB Jahmyr Gibbs). The Bills boast the reigning rushing king, James Cook, while Detroit comes to Western New York with All-Pros in WR Amon-Ra St. Brown and LT Penei Sewell. If you prefer old-school defensive slugfests, Thursday night’s offering might cause heartburn.”

Lions vs. Bills betting trends

Buffalo is 1-0 ATS and 1-0 to the Over. The Bills have won the last five meetings against the Lions.

Last year, the Bills were 4-5 ATS at home. And they were 2-5 ATS as a home favorite. However, the Bills went 6-3 to the Over at home last year. And they were 5-2 to the Over as a home favorite.

For the Lions, they are 0-1 ATS after a disappointing finish against the Saints. They are 1-0 to the Over.

Detroit was 4-5 ATS on the road last season. The Lions went 2-4 ATS as a road underdog. They were 5-4 to the Under on the road in 2025, and 4-2 to the Under as a road underdog.

Keys to the Lions vs. Bills matchup

If the Bills want to have a shot, they will have to focus on Jahmyr Gibbs and force the Lions to throw more than they want to throw. The Lions will be content to move down the field with Gibbs as the catalyst. This will allow them to eat clock and keep Allen off the field.

Gibbs is coming off a career-high 29 carries and 34 total touches in Week 1. He totaled 186 total yards and two touchdowns. Receiver Amon-Ra St. Brown caught 10 passes for 67 yards and two touchdowns.

Bills head coach Joe Brady said he knows what is in store for his defense, according to billswire.com.

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“They’ve been a dynamic offense for a lot of years,” Brady said. “[Quarterback] Jared Goff does a great job running the show. And you see what Gibbs is able to do. They're dynamic as it gets.”

Bills linebacker Bradley Chubb said his team needs to win at the line of scrimmage.

“They got players at each level of the offense,” Chubb said. “They got key playmakers at each position. It's going to be big for us on defense to slow them down.”

As for the Lions, the face Allen and running back James Cook. Allen threw for 334 yards and two touchdowns while also rushing for 23 yards and a pair of scores in the wild win over the Texans.

Cook totaled 17 touches for 69 yards. And that was an off game for him.

What do the Lions say about the game?

Lions head coach Dan Campbell said it’s obvious what his defense needs to focus on when they’re on the field, according to fox2detroit.com.

“The guy that's that's under center or in shotgun for them poses a lot of issues to your defense. You know you have to check every box on your defense. He's got it all, and we have to be prepared for all of it. And if a mistake is made, we have to capitalize.”

Lineman Penei Sewell said the atmosphere at the Bills' brand-new stadium will be electric.

“You've got to handle the environment,” Sewell said. “Obviously, it's not going to change. It's going to, honestly, probably get louder. We've got to go out there and trust what we've been doing. Trust the preparation and communicate. That's the main thing. I know it's going get loud. But up front, we got to get on the same page.”

Lions vs. Bills Prediction and Pick

It might have been easier to see the Lions sneaking out with a win if they had finished stronger against the Saints. They were one 2-yard play away from losing.

Plus, the excitement about the new stadium will have every Bills player pumped. That means focus. They won’t want to lose their first game in a high-dollar, high-tech venue.

Look for the Lions to make it fun and interesting deep into the fourth quarter.

Bills 31, Lions 27