New Orleans Saints vs. Buffalo Bills Picks and Prediction, Sunday, September 28, 2025
Use Code WWWC On Sunday, the Buffalo Bills will host the New Orleans Saints at Highmark Stadium in an NFC vs. AFC clash, and we have you ready to go with our Saints vs. Bills prediction. Kickoff from Buffalo, NY, is at 1:00 p.m. ET.
The Bills are 15.5-point spread favorites, and the game total is 47.5 points scored.
This is the first matchup between these teams since 2021 in Louisiana, when Buffalo stomped New Orleans 31-6 as 6.5-point favorites. Bills QB Josh Allen passed for 260 yards and four touchdowns in that game, outgaining the entire Saints offense. The Saints won the previous three meetings in 2009, 2013, and 2017. If you want the Saints vs. Bills prediction, read on and check out our NFL Picks to beat the sportsbooks!
Can the Saints be more competitive this week?
New Orleans (0-3 SU, 0-3 ATS, and 2-1 O/U) kept its first two games close, losing 20-13 to Arizona and 26-21 to San Francisco, but was thoroughly outplayed last week at Seattle, losing 44-13. The Saints failed to cover the spread in those games as underdogs of 6.0 points, 3.0 points, and 7.5 points.
Get Free $30 Credit for Premium Picks + Exclusive Discounts
Subscribe Now
Last week's loss to the Seahawks was humbling, as the Saints were outgained despite running 16 more plays than the home team. Seattle made the most of its opportunities in the red zone (4-for-5), while New Orleans struggled to move the chains (combined 5-for-17 on third and fourth down). The Seahawks did their damage through the air, averaging 11.1 yards per pass. Rookie Trey Horton also found the end zone on a 95-yard punt return. It was another flag-filled afternoon for New Orleans, as the Saints were penalized 11 times after committing 20 penalties in their first two games.
“At this point, teams look at us as if we’re undisciplined,” defensive end Cameron Jordan said. “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.”
Spencer Rattler leads the Saints' passing game with 639 yards (67.2% CMP%), four touchdowns, and one interception. The South Carolina product's top receiving targets are TE Juwan Johnson (19 receptions for 176 yards and one TD) and WR Chris Olave (23 receptions for 165 yards). RB Alvin Kamara paces the New Orleans run game with 50 carries for 186 yards (3.7 YPC) and one score.
The Saints score 15.7 points per game (29th) and average 302.0 total yards (19th), including 199.7 passing yards (18th) and 102.3 rushing yards (19th). New Orleans' defense surrenders 30.0 points (25th) and 313.3 total yards (15th) per game, including 210.0 passing yards (18th) and 103.3 rushing yards (14th).
New Orleans Saints Football Injury Report: WR Devaughn Vele (hip) is questionable, and DE Chase Young (calf) and OL Dillon Radunz (toe) are out for Sunday's game against the Bills.
Buffalo ranks second in passing yards allowed
Buffalo (3-0 SU, 2-1 ATS, and 2-1 O/U) outlasted Miami 31-21 in its last game (Sept. 18), failing to cover as 11.0-point spread favorites. The Bills beat Baltimore 41-40 as one-point underdogs in Week 1 and demolished New York (AFC) 30-10 as 6.0-point favorites in Week 2.
Buffalo needed to lock in after halftime to beat the Dolphins, as the division rivals were all knotted up at 14 after two quarters. Miami was threatening to tie the score with just three minutes left, but LB Terrel Bernard intercepted QB Tua Tagovailoa’s pass to put the game away. The Bills were most effective on the ground (5.8 YPC), but Allen also passed for three touchdowns.
“Good win, never easy,” Bills head coach Sean McDermott said. “I thought the grit, the mental toughness of our football team was on display throughout the game, particularly in the fourth quarter there."
The former MVP leads the Buffalo offense with 755 passing yards (69.7% CMP%), four touchdowns, and zero picks. He has also rushed for 114 yards and two scores. Allen's top receiving targets are WR Keon Coleman (14 receptions for 158 yards and one TD) and TE Dalton Kincaid (13 receptions for 151 yards and two TDs). RB James Cook paces the Bills' ground game with 53 carries for 284 yards and four touchdowns.
Buffalo scores 34.0 points per game (4th) and averages 420.0 total yards (1st), including 257.0 passing yards (5th) and 163.0 rushing yards (1st). The Bills' defense allows 23.7 points (20th) and 287.3 total yards (9th) per game, including 131.3 passing yards (2nd) and 156.0 rushing yards (32nd).
Buffalo Bills Football Injury Report: RT Spencer Brown (calf) and DE A.J. Epenesa (pectoral) are questionable, and LB Matt Milano (pectoral) and DT Ed Oliver (ankle) are out for Sunday's game against the Saints.
Saints vs. Bills Pick
Spread Pick for Saints vs. Bills
- Buffalo -15.5 (5 Units)
New Orleans' defense has been unable to slow opponents' passing games, allowing an average passer rating of 118.9. If Kyler Murray, Mac Jones, and Sam Darnold can put up those numbers, Allen will make the Saints' secondary look like Swiss cheese. He has dominated against zone coverage (74.5% completion percentage), which NOLA plays often under DC Brandon Staley. The big, chunk plays will be available, too, as the Saints have surrendered eight passes of 20-plus yards and three of four-plus yards.
New Orleans would be best served to run the football on Sunday, as the Bills have not defended the run well. With Oliver sidelined, that isn't likely to change soon, either. However, if the Saints fall behind early, they won't be able to stick to the ground game. That isn't in the visitors' best interest, as Rattler isn't reliable enough to move the chains through the air. That's especially true against this stout Bills pass defense.
I expect Buffalo to cruise to a home win after a mini bye week, covering the 15.5-point spread.
Over/Under Pick for Saints vs. Bills
- Under 47.5 (4 Units)
I don't envision New Orleans being competitive enough on Sunday to push the total over 47 points. The Saints rank near the bottom of the NFL in EPA per play and success rate, and they won't have the luxury of running the football much against the Bills' soft run defense when the home team inevitably jumps out to an early lead. The visitors have been penalized too often to move the chains, and I doubt they'll play cleaner football this week. The Bills will rely more on the run game with a big lead in the second half, bleeding the game clock.
Betting on the NFL?
- Be sure to look our our list of the best NFL online sportsbooks
- Grow your bankroll by claiming one of our favorite NFL sportsbook promo codes
Up To $1500 in Bonus Bets Paid Back if your First Bet Does Not Win
New Users – Bet $5 Get $200 in Bet Reset Tokens for 5 Days
