New Orleans Saints vs Buffalo Bills Prediction, Odds and Picks for Tomorrow, 09/28/25

The most lopsided game of the slate by a wide margin on paper comes in Buffalo where the Bills will host the Saints in a game between arguably the best and worst teams in the NFL. Buffalo has already raced out to a 3-0 start, and despite the fact that the Bills clearly have some clear flaws on defense and some questions within their wide receiving corps, this is still an elite team with the reigning MVP at the controls. At this point, Josh Allen’s Hall of Fame resume is nearly set in stone, and the Bills quarterback leads an offense that is 3rd in EPA per play, 1st in EPA margin, 3rd in success rate and inside the top 10 in total touchdowns. He’ll be going up against a Saints defense that has struggled mightily to this point, despite facing a very pedestrian schedule of offenses. It goes without saying that this won’t be the case on Sunday, especially in a building where the Bills routinely score 30+ points.

As for the New Orleans offense, this is a unit that couldn’t get anything going a week ago in Seattle. And while the Buffalo defense is certainly worse than what the Seahawks have to offer, the Bills should be able to key in on stopping the Saints ground game, which should force Spencer Rattler to take risks and turn the ball over at least a time or two as a result. It’s not often that I’ll ever look to lay more than two touchdowns in an NFL game, but I can only look toward the home side in this matchup.

Saints vs Bills prediction: Bills -15.5 available at time of publishing. Playable to -16.

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In a game like this, there is always the chance that the Bills put up a massive number on the scoreboard. However, I’m opting to side with the under in Buffalo given how poor the Saints offense has been to this point. New Orleans is near the bottom of the league in EPA per play and success rate on offense, which should give the Bills defense a bit of a break after having already faced the Ravens and a Dolphins offense that has a lot of talent and speed, even if the results haven’t been there. As for the Buffalo offense, this is a unit that will likely just look to grind the game out once they establish a significant lead in the second half, so the clock should be running as we near the conclusion of this one.

Under 48.5 available at time of publishing. Playable to 48.