Best NFL Picks and Predictions for Patriots vs. Bills on Sunday Night Football in Week 5

Breaking down the best picks and predictions for the New England Patriots-Buffalo Bills matchup on Sunday night.

The New England Patriots are underdogs in Week 5. / Bob DeChiara-Imagn Images

The New England Patriots and Buffalo Bills face off in a crucial AFC East matchup on Sunday Night Football in Week 5, and the Bills are sizable favorites in the latest odds. 

Buffalo is undefeated through four weeks, but it has failed to cover the spread as a double-digit favorite in each of the last two games heading into Week 5. Meanwhile, the Patriots are back to .500 in 2025 after knocking off the Carolina Panthers in Week 4. 

Drake Maye and the Patriots would love to make a statement in Week 5 on the road, but Josh Allen and the Bills have the No. 1 offense in EPA/Play in the 2025 season. So, things won’t come easy for the Pats on the defensive side on Sunday night. 

Allen has won five of the last six games he’s played against the Pats (not including the loss in Week 18 last season when he played just one series). Can the Bills build on that and move to 5-0?

The SI Betting team has you covered when it comes to betting on this game, as we’ve broken down several interesting plays for this AFC East clash.  

Best NFL Picks and Predictions for Patriots vs. Bills

Odds via DraftKings Sportsbook and BetMGM.

• New England Patriots Moneyline (+370) vs. Buffalo Bills – Iain MacMillan
• Stefon Diggs Anytime TD (+205) – Peter Dewey
• James Cook OVER 100.5 Rushing and Receiving Yards (-115) – Ryan Gilbert

New England Patriots Moneyline (+370) vs. Buffalo Bills – Iain MacMillan

Earlier this week, SI’s NFL betting insider Iain MacMillan made the case for a Patriots upset win in his Road to 272 column: 

It's been a while since I've made this bold of an upset pick, but I see a lot of issues with this Bills team. Let's remember how weak their schedule has been since Week 1. Their last three games have come against the Jets, Dolphins, and Saints. Despite that, they rank only seventh in Net Yards per Play (+0.9), and their defense ranks 22nd in opponent EPA per play, 17th in opponent success rate, and 22nd in defensive DVOA. To have those numbers while playing three of the worst teams in the NFL is a real problem.

Meanwhile, Drake Maye has had a fantastic start to his sophomore season. He's sixth amongst starting quarterbacks in EPA+CPOE composite and adjusted EPA per play. Their defense has had some problems of its own, but they rank right around the same as the Bills in several categories.

This has all the makings of an offensive shootout, and if the Bills aren't careful, the Patriots have a chance of pulling off an AFC East upset. I'll take a shot on New England as a big-time underdog.

Stefon Diggs Anytime TD (+205) – Peter Dewey

This is a revenge game for Stefon Diggs, and he’s coming off his best game of the season, making him an intriguing bet to score on Sunday night: 

A former Bill, Stefon Diggs is starting to find his footing in New England, catching six passes on seven targets for a season-high 101 yards in Week 4. 

Now, he’s taking on a Buffalo defense that has given up six passing scores in the 2025 season and struggled a bit against Tua Tagovailoa and Spencer Rattler in the last two weeks. 

Diggs is starting to break out as the No. 1 receiver in New England, and he played a season-high 63.3 percent of the snaps in Week 4 as he works his way back from a torn ACL.

I think this is a great spot for him to score for the first time in 2025. 

James Cook OVER 100.5 Rushing and Receiving Yards (-115) – Ryan Gilbert

SI Betting’s Ryan Gilbert shared his favorite prop for this game earlier on Sunday, and he’s backing Bills running back James Cook: 

James Cook has been tremendous out of the backfield for the Bills this season. He’s ran for 401 yards this year, including over 100 in each of the last three weeks. Even in Week 1 when he ran for 44 yards, he picked up 58 receiving to go Over 100.5 total yards.

The Patriots have defended running backs fairly well this season, holding Ashton Jeanty to 38 yards on 19 carries in his NFL debut, and Jaylen Warren and Chubba Hubbard each under 50 yards in the last two weeks.

But it’s Week 2 against the Dolphins that is the best comparable for Cook. Miami’s De’Von Achane had eight catches for 92 yards and a score along with 30 yards on the ground.

Cook should keep up his hot start to the season, whether it’s on the ground or through the air.

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Odds refresh periodically and are subject to change.

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