Saints vs. Bills Prediction, Odds, Spread, Injuries, Trends for NFL Week 4

Iain MacMillan | Sep 23, 2025

Josh Allen and the Bills are massive favorites against the Saints in Week 4. / Chuck Cook-Imagn Images

The Buffalo Bills will host the New Orleans Saints in what is arguably a game between the best and worst teams the National Football League has to offer. As a result, we see what might just be the largest spread we'll see in the league this season.

Let's dive into the odds and my best bet for this lopsided Week 4 affair.

Saints vs. Bills Odds, Spread, and Total

Odds via Caesars Sportsbook

Spread

• Saints +16.5 (-110)
• Bills -16.5 (-110)

Moneyline

• Saints +1050
• Bills -2000

Total

• OVER 47.5 (-110)
• UNDER 47.5 (-110)

Saints vs. Bills How to Watch

• Date: Sunday, Sept 28
• Game Time: 1:00 pm ET
• Venue: Highmark Stadium
• How to Watch (TV): CBS
• Saints Record: 0-3
• Bills Record: 3-0

Saints vs. Bills Betting Trends

• Saints are 1-5 ATS in their last six games
• The UNDER is 6-3 in the Saints' last nine games
• Saints have lost seven straight games
• Saints are 5-1 SU and ATS in their last six games vs. Bills
• Bills are 12-6 ATS in their last 18 games
• The OVER is 4-1 in the Bills' last five games
• Bills have won 12 straight home games

Saints vs. Bills Injury Reports

Saints Injury Report

• Chase Young, DE - Questionable
• Devaughn Vele, WR - Questionable
• Dillon Radunz, OT - Questionable
• Trey Palmer, WR - Questionable
• Taliese Fuaga, OT - Questionable

Bills Injury Report

• Ed Oliver, DT - Questionable
• Matt Milano, LB - Questionable
• Tyler Bass, K - IR
• DeWayne Carter, DT - IR
• Wande Owens, S - IR

Saints vs. Bills Key Player to Watch

• Josh Allen, Quarterback - Buffalo Bills

The defending NFL MVP is already off to an MVP-worthy 2025 campaign. The Bills are 3-0, and Allen has played some of the best football of his career. He's racked up 755 yards through the air, five touchdowns, 114 rushing yards, two rushing touchdowns, and most importantly, zero turnovers. As long as he doesn't have an uncharacteristically bad start, he's going to lead the Bills to another stress-free victory.

Saints vs. Bills Prediction and Pick

In this week's edition of the Road to 272 Bets, I broke down why I'm not afraid to lay the big number on the Bills:

There's a chance this game ends up being the biggest spread of the entire season, but that's not going to scare me away from laying the points on this one. This very well might be the worst team in the league on the road against the best team.

After two straight weeks of being relatively in the game, the Saints showed their true colors in Week 3 when they were completely steamrolled by the Seattle Seahawks. Their road trip now heads to Buffalo, the team that leads the league in EPA per play.

There's nothing the Saints can do to remain competitive in this game with Spencer Rattle as their quarterback. Unless the Bills have an F performance, they'll run away with this one.

Pick: Bills -16.5 (-110) via Caesars

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