Buffalo Bills vs. New Orleans Saints predictions, odds, and picks for Week 4 showdown

The Buffalo Bills (3-0) host the New Orleans Saints (0-3) in what is expected to be one of the most one-sided contests of Week 4. The Bills are looking like a Super Bowl-contending outfit, while the Orleans are headed in the exact opposite direction, going winless to start the season.

Bills are the overwhelming favorites heading into the contest as we examine predictions, odds, and picks for the Week 4 showdown.

Buffalo Bills vs. New Orleans Saints: Game Details

Date and Time: Sunday, September 28, 2025, at 1:00 pm ET

Looking to predict NFL playoff Scenarios? Try our NFL Playoff Predictor for real-time simulations and stay ahead of the game!

Game: Buffalo Bills vs. New Orleans Saints

Venue: Highmark Stadium, Orchard Park, New York

Buffalo Bills vs. New Orleans Saints: Betting Odds (Caesars Sportsbook)

Moneyline: Buffalo Bills (-2000), New Orleans Saints (+1050)

Spread: Buffalo Bills -16.5 (-110), New Orleans Saints +16.5 (-110)

Total: 47.5 (Over/Under: -110/-110)

Buffalo Bills vs. New Orleans Saints: Picks

The Bills have been dominant this season with defending NFL MVP Josh Allen leading the offense. Allen is making a strong case for consecutive MVP titles after racking up 755 passing yards, five touchdowns, 114 rushing yards and two rushing touchdowns.

With Allen in red-hot form, expect the Bills to cover the spread (-16.5) and register a routing win against a hapless Saints.

Buffalo Bills vs. New Orleans Saints: NFL Injury Report

Buffalo Bills injury report:

LB Matt Milano (pectoral) - Out

DT Ed Oliver (ankle) - Out

RT Spencer Brown (calf) - Questionable

DE A.J. Epenesa (pectoral) - Questionable

New Orleans injury report:

DE Chase Young - Questionable

WR Devaughn Vele - Questionable

OT Dillon Radunz - Questionable

WR Trey Palmer - Questionable

OT Taliese Fuaga - Questionable

Buffalo Bills vs. New Orleans Saints: Prediction for Week 4

The Bills are expected to make light work of the Saints, who have been one of the worst teams on the road this season. They were dispatched by the Seattle Seahawks in their Week 3 game after a fast start from Seattle.

Expect Buffalo to make a similar start against the visitors with Josh Allen leading a dominant Bills offense. In their last meeting, the Bills thrashed the Saints for a 31-5 win at the Superdome in 2021.

The Saints are on a seven-game losing streak that started last season and has been outscored 196-95 during that stretch. Barring an uncharacteristically bad performance from Buffalo, the Bills are expected to cruise in this game.

Score prediction: Buffalo Bills 34, New Orleans Saints 15

About the author

Chaitanya Prakash is an editor who covers US Sports at Sportskeeda. His first brush with sportswriting was in 2012 when the greatest football manager of all time, Sir Alex Ferguson, bid farewell to the beautiful game.

Although having started out professionally as a cricket writer in 2022, Chaitanya's curiosity and indiscriminate interest in all sports in general eventually introduced him to America's favorite pastime.

While Chaitanya's favorite player from the current crop is the dynamic Venezuelan Ronald Acuna Jr., his all-time favorite, however, is Pedro Martinez, for his self-belief and consistency. He also rates Jose Bautista's iconic bat flip in 2015 as his favorite moment in baseball history.

Chaitanya specializes in reporting on technical aspects of the game or analyzing patterns behind specific plays. He also likes pondering over players' self-assessments following the conclusion of a game as it helps him get an idea of how they think about the sport in general.

When not cheering for his favorites across sports, Chaitanya likes being transported to the past through a good war documentary or a historical documentary in general.

Know More

Buffalo Bills Nation! Check out the latest Buffalo Bills Schedule and dive into the latest Bills Depth Chart for NFL Season 2024-25.

Edited by Chaitanya Prakash