The Buffalo Bills will host the New Orleans Saints in Week 4 of the NFL season. The Bills roll into Week 4 with momentum after a 3-0 start, while the Saints are reeling at 0-3. Buffalo is the biggest favorite on the Week 4 board by a wide margin and will look to justify that by putting a hurting on one of the worst teams in the NFL. Before the action begins in Orchard Park, continue reading to get my Saints vs Bills prediction.
Our Saints vs Bills Pick
- Pick: Buffalo Bills −15.5
- Confidence: ★★★☆☆
Game Snapshot
- Matchup: New Orleans Saints at Buffalo Bills
- Date & Time: Sunday, September 28, 2025, 1:00 PM ET
- Venue: Highmark Stadium, Orchard Park, NY
- Broadcast: CBS
Saints vs Bills Odds
| Spread | Moneyline | Total |
|---|---|---|
| Bills −15.5 | Bills −1600 / Saints +800 | 47.5 |
Key Storylines
- Bills’ home dominance: Buffalo has won its first three games and has gone 2-0 at home. They have averaged 34 points per game early in the season and are expected to put up another big number against a New Orleans defense that has been unable to slow down opposing offenses so far.
- Saints’ special teams and penalties: The Saints’ Week 3 loss to the Seattle Seahawks exposed serious issues that go well beyond the quarterback position. New Orleans allowed a blocked punt, a 95-yard punt return TD, and committed 11 penalties for 77 yards. Attention to detail is important in any football game and will be even more important against an elite team like the Bills.
- Momentum and rest: Buffalo has had extra rest since its last game after playing on Thursday night in Week 3. New Orleans is on the road for the second straight game and that could be a problem for a team with no shortage of problems.
Quarterback Play
Buffalo: Josh Allen continues to look sharp for Buffalo. In Week 3 against Miami he threw three touchdowns, no interceptions, and contributed with his legs as well. He’s playing with rhythm and is on the same page as his weapons early on.
New Orleans: Spencer Rattler has had mixed results for the Saints. In the Seattle game last week, he completed 28 of 39 passes for 218 yards, one touchdown, and one interception. But most of that game was garbage time for Rattler and the Saints given how far behind they fell early on. Rattler will have his hands full on the road against the Bills here.
Betting Trends & H2H
- The Bills are 2-1 against the spread this season.
- The Saints are 0-3 ATS through three weeks.
- Both teams have gone over the total in two of their first three games this year.
Saints vs Bills Model Projection
| Score Projection: | Buffalo 35 – New Orleans 13 |
| Win Probability: | Buffalo 90%, Saints 10% |
Final Thoughts
Buffalo is the superior team by a wide margin entering this matchup. The gap in execution, roster depth, and momentum is wide between these teams. The Bills are unlikely to let this game get close unless they completely fall apart, which doesn’t seem likely given how smoothly they’ve been operating. I recommend laying the biggest number on the board this week with Buffalo at home.
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- Source: https://ats.io/nfl/new-orleans-saints-vs-buffalo-bills-prediction-9-28-2025/468018/