The Buffalo Bills will lock horns with the New Orleans Saints in Week 4 of the NFL season at Highmark Stadium on Sunday September 28. Kickoff is at 1 p.m. ET.

Following the Bills’ narrower-than-expected victory over the Dolphins on Thursday Night Football and the Saints’ blowout loss to Seattle on Sunday, Dimers’ analysts conducted preliminary simulations for the Bills vs. Saints in Week 4.

The results were compared to current NFL odds from sportsbooks like Bet365, DraftKings, and FanDuel, to inform the Bills-Saints preview below.

Saints vs. Bills betting preview

Utilize the interactive widget below to discover the current spread, total, and moneyline odds and probabilities for the Saints-Bills matchup at Highmark Stadium.

Game details

Key information on the Saints vs. Bills matchup, including where the game is and what time it kicks off.

Teams: New Orleans Saints vs. Buffalo BillsDate: Sunday, September 28, 2025Kickoff: 1 p.m. ETLocation: Highmark StadiumNFL standings: Current NFL division standingsNFL injuries: Check the latest updates to the official NFL injury reportOdds

The latest and best odds for the NFL matchup between the Saints and Bills.

Spread: Saints +12.5 (-110), Bills -12.5 (-110)Moneyline: Saints +490, Bills -675Total: Over/Under 46.5 (-110/-110)

The odds and lines presented in this article are the best available from selected sports betting sites at the time of publication and are subject to change.

Expert prediction: Saints vs. Bills

Utilizing trusted data analysis and advanced algorithms, the experts at Dimers have executed 10,000 simulations of the Saints vs. Bills matchup.

According to Dimers’ popular predictive analytics model, the Bills are more likely to defeat the Saints at Highmark Stadium. This prediction is based on the model giving the Bills an 85% chance of winning the game.

Furthermore, Dimers predicts that the Saints (+12.5) have a 53% chance of covering the spread, while the 46.5-point over/under has a 53% chance of staying under.

As always, these predictions and probabilities are correct at the time of publication but are subject to potential changes.

Saints vs. Bills best bet

Our top pick for the Saints vs. Bills Week 4 NFL game is to bet on Under 46.5 points (-110).

This expert betting advice is based on comprehensive simulations and valuable wagering intelligence, designed to assist you in making more informed investments.

Score prediction for Saints vs. Bills

Dimers’ projected final score for the New Orleans vs. Buffalo game on Sunday has the Bills winning 27-17.

This expert prediction is based on each team’s average score following 10,000 game simulations, offering a glimpse into the potential outcome.

NFL Week 4: Saints vs. Bills

Get ready for Sunday’s matchup between the Saints and Bills in Week 4 of the NFL season at Highmark Stadium, which is scheduled to start at 1 p.m. ET. We emphasize that all of the NFL predictions and NFL best bets in this preview are based on 10,000 data-driven simulations of the Saints vs. Bills matchup, and they are accurate at the time of publishing. They aim to assist you make better decisions when placing bets at online sportsbooks.

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