The Buffalo Bills will take on the New Orleans Saints in Week 4 of the NFL season at Highmark Stadium on Sunday, scheduled to start at 1 p.m. ET.
All week, questions about the status of Bills right tackle Spencer Brown and defensive end A.J. Epenesa have dominated headlines.
With both Brown and Epenesa remaining questionable for Week 4, linebacker Matt Milano has been ruled out, as has defensive tackle Ed Oliver.
Following these updates, Dimers analysts conducted 10,000 new simulations of the Bills vs. Saints matchup early Sunday morning. The results were compared to current odds to inform the data-driven Bills-Saints preview below.
Saints vs. Bills betting preview
This preview includes Dimers’ best bets and predicted scoreline for the New Orleans Saints vs. Buffalo Bills, plus projected stats for the starters on both teams.
Explore the interactive widget below to discover the current spread, over/under, and moneyline odds and probabilities for the Saints-Bills game at Highmark Stadium.
Check out all the important details on today’s game, as well as the best odds sourced from the top sportsbooks in the country.
Game details
The key information you need before the Saints vs. Bills NFL game.
Teams: New Orleans Saints vs. Buffalo Bills
Date: Sunday, September 28, 2025
Kickoff: 1 p.m. ET
Location: Highmark Stadium
NFL standings: Current NFL division standings
NFL injuries: Check the latest updates to the official NFL injury report
Odds
Odds for the key markets in the Saints-Bills NFL game.
Spread: Saints +15.5 (-110), Bills -15.5 (-110)
Moneyline: Saints +900, Bills -1450
Total: Over/Under 48.5 (-104/-115)
The odds and lines featured here are the best available from selected sports betting sites at the time of publication and are subject to change.
Local Bills fans can unlock bonus bets and a $200 NFL Sunday Ticket discount with theses promos from DraftKings and FanDuel, while the Bet365 bonus code “SYRACUSE” unlocks $200 in bonus bets for Saints fans in Louisiana.
Expert prediction: Saints vs. Bills
Leveraging cutting-edge data analysis and advanced algorithms, the experts at Dimers have executed 10,000 simulations of Sunday’s Saints vs. Bills matchup.
According to Dimers’ independent 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 89% chance of winning the game.
Furthermore, Dimers predicts that the Saints (+15.5) have a 56% chance of covering the spread, while the over/under total of 48.5 points is considered an equal 50-50 chance of hitting.
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 matchup is to bet on the Saints +15.5 (-110).
This betting advice is based on cutting-edge modeling and valuable wagering intelligence, designed to bring you the best possible plays.
Score prediction for Saints vs. Bills
Dimers’ predicted final score for the New Orleans vs. Buffalo game on Sunday has the Bills winning 31-17.
This expert prediction is based on each team’s average score following 10,000 game simulations, offering a glimpse into the potential outcome.
Stat projections: Bills vs. Saints NFL Week 4
Below are the most likely first and anytime touchdown scorers for the Saints and Bills, along with projected player stats.
New Orleans Saints
First touchdown scorer predictions
Alvin Kamara: 9.0% probability
Juwan Johnson: 5.2% probability
Chris Olave: 4.9% probability
Anytime touchdown predictions
Alvin Kamara: 38.4% probability
Juwan Johnson: 24.2% probability
Chris Olave: 23.2% probability
Projected box score leaders
QB passing yards: Spencer Rattler, 217 yards
Receiving yards: Chris Olave, 65 yards
Rushing yards: Alvin Kamara, 56 yards
Buffalo Bills
First touchdown scorer predictions
James Cook: 15.0% probability
Josh Allen: 11.7% probability
Keon Coleman: 5.8% probability
Anytime touchdown predictions
James Cook: 59.9% probability
Josh Allen: 50.8% probability
Keon Coleman: 29.7% probability
Projected box score leaders
QB passing yards: Josh Allen, 230 yards
Receiving yards: Keon Coleman, 48 yards
Rushing yards: James Cook, 78 yards
NFL Week 4: Saints vs. Bills
Get ready for Sunday’s matchup between the Saints and Bills in Week 4 of the National Football League season at Highmark Stadium, which is scheduled to start at 1 p.m. ET.
Please note that when engaging in online betting, it is important to exercise responsible gambling practices and seek reliable sources for accurate and up-to-date information.
