If the Buffalo Bills hope to cover a massive spread against the New Orleans Saints, they’ll need every point they can muster.
Oddsmakers have installed a hefty line in Week 4 — a justified number with these teams sitting at opposite ends of the NFL power rankings.
With the home team laying more than two touchdowns, my Saints vs. Bills predictions and NFL picks are specifically targeting Buffalo wideout Keon Coleman.
Saints vs Bills prediction
Saints vs Bills Best bet: Keon Coleman Over 41.5 receiving yards (-114)
Buffalo Bills wideout Keon Coleman has cooled since a sizzling season debut. He snatched eight balls on 11 targets for 112 yards versus Baltimore in Week 1, but finished with only six catches for a total of 46 yards in wins over the Jets and Dolphins.
With a spread this big, you tend to shy away from the Over on passing props. The game script says Buffalo builds a big lead and protects that with a run-heavy playbook in the second half.
However, in order to build that buffer, the Bills need some quick yards.
The New Orleans Saints' defense is dreadful, yet it has been able to slow down opponents on the ground. The Saints rank 13th in run stop at PFF, ninth in EPA allowed per handoff, and sixth in opponent success rate per run.
Defending the pass has been a different story for NOLA.
This secondary has been sliced up, watching rival QBs boast an average passer rating of 118.9. New Orleans has almost exclusively used zone coverage in the secondary under new defensive coordinator Brandon Staley, getting picked apart by the likes of Mac Jones in Week 2.
Josh Allen is a massive step up in QB competition, especially when you consider how well Allen does versus zone schemes. More than 65% of his total passing yards have come versus zone (averaging 7.2 yards per pass), and he sits sixth in completion rate against zone coverage (74.5%) through three weeks.
New Orleans has contained shorter looks, ranking among the better defenses versus slot receivers. It’s been the outside WRs burning New Orleans for bigger gains. The Saints have given up eight passes of 20 or more and three of 40+ yards.
Enter Allen’s bazooka arm and Coleman’s big-play potential. The wideout is a home run threat and could take a big chunk out of his yardage prop with just one catch Sunday. Coleman’s player models all sit north of 40 yards, with a high of 57.
Saints vs Bills same-game parlay
Coleman could knock out a lot of this total on one big play against a bad Saints secondary.
Coleman found the end zone in Week 1, and I like him to strike again in Week 4.
Allen will air it out and pick apart this zone-heavy Saints scheme.
Saints vs Bills 3-leg SGP
- Keon Coleman Over 41.5 receiving yards
- Keon Coleman anytime touchdown
- Josh Allen Over 216.5 passing yards
Our big-ticket SGP: Aerial assault
Coleman’s projections all sit north of this total, with some at 50+ yards. After two quiet weeks, Coleman comes back with a bang. Allen is fantastic against zone and projected for more than 230 passing yards. Meanwhile, Alvin Kamara and the Saints could try to play keep-away on the ground.
Saints vs Bills 4-leg SGP
- Keon Coleman Over 41.5 receiving yards
- Keon Coleman anytime touchdown
- Josh Allen Over 216.5 passing yards
- Alvin Kamara Over 50.5 rushing yards
Saints vs Bills game predictions
Saints vs Bills moneyline prediction
This is a beefy ask on the outright price, with Buffalo listed as a -1500 moneyline favorite. That means you’d need to wager $1,500 to win $100. Too expensive for my blood.
That price tag comes with an implied win probability of 93.75%. The Bills are rested and ready after a mini bye and should cruise to an easy win. Buffalo 29, New Orleans 13.
Saints vs Bills spread prediction
Rarely do we see spreads this big this early.
Bookies opened this game with the Bills as 14.5-point home favorites, and that jumped all the way to -17 at some shops before buyback on NOLA dropped the line to -15.5.
Since 2010, there have been just 12 favorites of more than two touchdowns (-14.5 or higher) in the opening four weeks, and those heavy faves went 7-4-1 ATS.
Saints vs Bills Over/Under prediction
Buffalo can come out swinging and build a quick lead before slowing things down and protecting first-teamers in the second half.
The Saints could try to play keep-away with a ground-focused offense, looking to poke the Bills’ defensive soft spot. T
That could also keep gains short and the clock ticking. I like the Under 48.5.
Saints vs Bills odds
- Spread: Saints +17.5 (-105) | Bills -17.5 (-115)
- Moneyline: Saints +1100 | Bills -2500
- Over/Under: Over 48.5 (-110) | Under 48.5 (-110)
More NFL picks and odds from Covers
Saints vs Bills trend to know
Favorites of -14.5 or more are 11-1 SU and 7-4-1 ATS in the opening four weeks since 2010. Funny enough, that lone SU loss came courtesy of Buffalo. The Bills lost outright as 16.5-point chalk to Minnesota in Week 3 of the 2018 season. Find more NFL betting trends for Saints vs. Bills.
How to watch Saints vs Bills
| Location | Highmark Stadium, Orchard Park, NY |
| Date | Sunday, September 21, 2025 |
| Kickoff | 1:00 p.m. ET |
| TV | CBS |
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