New Orleans Saints vs. Buffalo Bills early prediction: Expert picks for NFL Week 4, 2025

The New Orleans Saints and Buffalo Bills will meet in Week 4 of the NFL season at Highmark Stadium on Sunday, September 28, 2025, starting at 1:00PM ET.

Early simulations from Dimers' trusted NFL model favor the Bills as the most likely winner of this matchup.

For updates all week long, including best bets, player prop projections and touchdown probabilities, check out our interactive Saints vs. Bills predictions page.

New Orleans vs. Buffalo early predictions

Leveraging trusted machine learning and analysis, we have simulated the Saints vs. Bills game 10,000 times as part of our NFL predictions coverage. Here are the latest insights:

• Straight up win probabilities: Saints 15%, Bills 85%
• Predicted final score: Saints 17-27 Bills
• Spread: Saints (+12.5) 53%, Bills (-12.5) 47%
• Total points (46.5): Over 47%, Under 53%

As of September 21, 2025, these Saints-Bills figures and predictions reflect the latest data and insights available.

Saints vs. Bills Week 4 details

The NFL Week 4 game between the Bills and Saints at Highmark Stadium is scheduled for September 28, 2025.

• Who: New Orleans Saints vs. Buffalo Bills
• Date: Sunday, September 28, 2025
• Time: 1:00PM ET/10:00AM PT
• Venue: Highmark Stadium

Saints vs. Bills opening odds

We've researched the best betting odds across America for this Week 4 game, which are listed here:

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

Odds may continue to move—track live changes via our NFL odds page.

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Conclusion

We predict the Bills, with an 85% win probability, will likely beat the Saints in Week 4 of the NFL season. Dimers.com will provide full game coverage closer to kickoff, so stay tuned for updates.

Enhanced by AI and automation, this article delivers quick, accurate insights on the Saints vs. Bills game, with human oversight maintaining high editorial quality. Our predictions are based on the latest data to help you make informed decisions. For additional resources and advice on responsible gambling, please call 1-800-GAMBLER.

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