Patriots vs. Bills Prediction, Odds, Spread, Injuries, Trends for NFL Week 5

Iain MacMillan | Sep 30, 2025

Drake Maye and the Patriots are road underdogs against the Buffalo Bills on Sunday Night Football in Week 5. / Mark Konezny-Imagn Images

The New England Patriots are fresh off an impressive 42-13 win against the Carolina Panthers in Week 4, but they now have an extremely tough challenge ahead of them in Week 5 when they head to Buffalo to take on the Bills on Sunday Night Football.

The Bills have gotten off to a 4-0 start this season, but have failed to cover a big favorites the past two weeks. They're once again set as significant favorites when they host their AFC East rival.

Let's dive into the odds and my best bet for this game.

Patriots vs. Bills Odds, Spread, and Total

Odds via BetMGM Sportsbook

Spread

• Patriots +7.5 (-110)
• Bills -7.5 (-110)

Moneyline

• Patriots +325
• Bills -425

Total

• OVER 49.5 (-115)
• UNDER 49.5 (-105)

Patriots vs. Bills How to Watch

• Date: Sunday, Oct. 5
• Game Time: 8:20 pm ET
• Venue: Highmark Stadium
• How to Watch (TV): NBC
• Patriots Record: 2-2
• Bills Record: 4-0

Patriots vs. Bills Betting Trends

• The OVER is 8-3 in the Patriots' last 11 games
• Patriots are 4-1 ATS in their last five games vs. Bills
• Patriots are 2-7 straight up in their last nine road games vs. Bills
• The OVER is 4-1 in the Patriots' last five divisional games
• The OVER is 5-1 in the Bills' last six games
• Bills have won 13 straight games at home

Patriots vs. Bills Injury Reports

Patriots Injury Report

• Jared Wilson, C - Questionable
• Layden Robinson, G - IR
• Jahlani Tavai, LB - IR-R
• Isaiah Iton, DT - IR
• Deneric Prince, RB - IR

Bills Injury Report

• Cameron Johnston, P - IR
• Ed Oliver, DT - Questionable
• Matt Milano, LB - Questionable
• Spencer Brown, OT - Questionable
• Tyler Pass, K - IR

Patriots vs. Bills Key Player to Watch

• Drake Maye, QB - New England Patriots

Hiding behind a Patriots' average start to the season has been a great start to Drake Maye's sophomore campaign. He has completed 74% of passes while averaging 247 passing yards per game, tossing seven touchdowns and two interceptions. That's all while playing behind an offensive line that has allowed him to be sacked 13 times. By all accounts, he has taken a step forward this season, making him one of the more fascinating players to watch the rest of the season.

Patriots vs. Bills Prediction and Pick

In this week's edition of the Road to 272 Bets, I broke down why I think the Patriots are worth a bet to not only cover the spread, but win this game outright in one of the biggest upsets of the season:

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.

Pick: Patriots +325 via BetMGM

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