by Rod Pearson
Thursday, Sep 25, 2025
Game Time: 1:00 pm ET, Sunday, September 28, 2025
Venue: Highmark Stadium, Orchard Park, NY
Where to Watch: CBS
Opening Odds at USA Sportsbooks
DraftKings: Point Spread: Saints +15.5, Bills -15.5; Over/Under: 47.5 points
Bet365: Point Spread: Saints +15.5, Bills -15.5; Over/Under: 48 points
BetMGM: Point Spread: Saints +15.5, Bills -15.5; Over/Under: 48 points
Season Record
New Orleans Saints: 0-3 (4th place, NFC South)
Buffalo Bills: 3-0 (1st place, AFC East)
Do not miss out on our expert handicapper analysis! Amedeus Mastrangelo is on a HOT STREAK in the NFL on a 19-11-1 NFL RUN for +$7,020 PROFIT! Make sure you check out his picks and many more from the expert handicappers featured in the Shop Picks section.
Recent Form
New Orleans Saints: lost their last game on the road against the Seattle Seahawks 44-13.
Buffalo Bills: won their last game at home against the Miami Dolphins 31-21.
New Orleans Saints vs Buffalo Bills Preview and Analysis
The Saints are entering this game with a 0-3 record overall and they have a 0-0 record in their divisional games too. They are 0-2 in their home games, 0-1 in their road games, and they are also 0-0 in their neutral site games this season, but they will be on the road for this game. They lost their last game against the Seattle Seahawks 44-13. Spencer Rattler was the starting QB and he completed 28/39 passes for 218 passing yards, 1 touchdown, and 1 interception. Alvin Kamara led the team in rushing yards with 42. Chris Olave led the receivers with 57 receiving yards on 10 receptions. Pete Werner led the defense in that game with 7 solo tackles and 6 assisted tackles while no one on the defense recorded a sack for them. No one on the defense came away with an interception for them in that one.
The Bills are entering this game with a 3-0 record overall and they have a 2-0 record in their divisional games too. They are 2-0 in their home games, 1-0 in their road games, and they are also 0-0 in their neutral site games this season, but they will be at home for this game. They won their last game against the Miami Dolphins 31-21. Josh Allen was the starting QB and he completed 22/28 passes for 213 passing yards, 3 touchdowns, and 0 interceptions. James Cook led the team in rushing yards with 108 and 1 TD. Dalton Kincaid led the receivers with 66 receiving yards on 5 receptions and 1 TD. Taron Johnson led the defense in that game with 6 solo tackles and 2 assisted tackles while no one on the defense recorded a sack for them. Terrel Bernard came away with the only interception for them in that one.
Saints vs Bills Prediction
The current betting odds have the Bills listed as a 15.5 point favorite in this game according to Draftkings Sportsbook. The Bills have looked great in their games this season with their 3-0 record overall which has them right at the top of the AFC East. They opened the season with a big comeback win at home over the Ravens and now they have won 2 games in a row by double digits. They look like one of the best teams in the NFL this season and they aren't going to be slowed down at home by one of the worst teams in the league. Meanwhile, the Saints have looked terrible in their games this season with their 0-3 record overall which has them right at the bottom of the NFC South. They are in their first year of a new head coach and they don't really have an answer at QB yet. They didn't look terrible in the first 2 weeks as they were in both games against the Cardinals and the 49ers, but they got split open in their first road game last week, losing 44-13 to the Seahawks. The Seahawks didn't have to do much to win that game with some of the mistakes the Saints were making, and the Bills are going to do the exact same thing at home with the talent they have. Look for the Bills to beat up on one of the worst teams in the NFL here at home and stay undefeated this season. The best way to place a bet here is on the Bills to cover the spread in this game.
Saints Bills Prediction: Our NFL Pick for Sunday, September 28, 2025 (1:00 pm ET start time) is Bills 45 Saints 10.
Don't miss our champion handicappers free picks and expert football picks today. And if you enjoyed this New Orleans Saints Buffalo Bills prediction, be sure to drop by every day for our weekly NFL predictions and previews.
NFL Betting Trends
New Orleans Saints: 26-12 ATS against AFC East division opponents. 27-17 ATS against teams with a turnover margin of +1 per game or better. 84-54 ATS vs. good offensive teams - scoring 24 or more points/game. 6-3 OVER in a road game where the total is between 42.5 and 49 points.
Buffalo Bills: 0-5 ATS as a favorite of 10 or more points. 0-8 ATS vs. bad defensive teams who give up 24 or more points/game. 0-7 ATS vs. poor teams - outscored by 6+ points per game on the season. 9-5 OVER in a home game where the total is greater than or equal to 45.5.
Key Injuries
New Orleans Saints: D. Radunz (OG) Injured - Toe. C. Young (DL) Injured - Calf. T. Fuaga (OT) Injured - Knee. T. Palmer (WR) Injured - Hamstring. D. Vele (WR) Injured - Hip. C. Jordan (DL) Injured - Groin. T. Penning (OG) Injured - Toe.
Buffalo Bills: S. Brown (OT) Injured - Calf. A. Epenesa (DL) Injured - Pectoral. M. Milano (LB) Injured - Pectoral. E. Oliver (DL) Injured - Ankle.
Notable Quotes
“At this point, teams look at us as if we’re undisciplined. If you’re a top-three most penalized team, that’s just a moniker they give you. We have to be able to be better.” - Cameron Jordan after their loss against the Seahawks in their last game.
“Good win, never easy. I thought the grit, the mental toughness of our football team was on display throughout the game, particularly in the fourth quarter there.” - Sean McDermott after his team’s win against the Dolphins in their last game.
Starting Lineups
New Orleans Saints
WR Olave, Chris
WR Cooks, Brandin
WR Shaheed, Rashid
TE Johnson, Juwan
QB Rattler, Spencer
RB Kamara, Alvin
Buffalo Bills
WR Palmer, Joshua
WR Coleman, Keon
WR Shakir, Khalil
TE Kincaid, Dalton
QB Allen, Josh
RB Cook, James
FB Gilliam, Reggie
Statistical Leaders
New Orleans Saints
Passing: Spencer Rattler (639)
Rushing: Alvin Kamara (186)
Receiving: Juwan Johnson (176)
Touchdowns: Alvin Kamara (1)
Buffalo Bills
Passing: Josh Allen (755)
Rushing: James Cook (284)
Receiving: Keon Coleman (158)
Touchdowns: James Cook (4)
Coaches:
New Orleans Saints: Kellen Moore (1st season)
Buffalo Bills: Sean McDermott (9th season)
Rod Pearson
About the Author:
Rod Pearson has been a rabid sports fan his entire life. He grew up in Ontario, and was skilled in both hockey and baseball, and pitched in an elite baseball league for many years. In 2022, Rod decided to hang up his glove, so that he could write about the sports he loves -- but from a gambling perspective. Join Rod every day as he breaks down the games to find the best betting value.
