Oddsmakers aren’t buying the “Any Given Sunday” mantra for one Week 4 matchup.
The New Orleans Saints aren’t given much of a chance to upset the Buffalo Bills this weekend. They’re a massive 16.5-point underdog on DraftKings Sportsbook and FanDuel Sportsbook.
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That gaping spread is actually growing, as it opened at 15.5.
Two teams in opposite directions
Sep 21, 2025; Seattle, Washington, USA; New Orleans Saints head coach Kellen Moore looks on during the second half against the Seattle Seahawks at Lumen Field. Mandatory Credit: Joe Nicholson-Imagn Images
No other Week 4 game has a double-digit spread, but it’s hard to create a more lopsided matchup than the one taking place at Orchard Park.
The Bills sit near the top of most NFL power rankings after a 3-0 start. They’ve averaged a league-leading 420 yards per game while allowing the ninth-fewest yards despite surviving a Week 1 shootout against the Baltimore Ravens.
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Buffalo followed a dramatic comeback over Baltimore with a 30-10 win over the New York Jets and a 31-21 triumph over the Miami Dolphins. For what it’s worth, the Bills registered six wins by more than 20 points last season.
On the other hand, the Saints are a leading candidate to receive next year’s No. 1 draft pick.
New Orleans is one of six teams saddled with a 0-3 record, and its minus-43 point differential matches the Tennessee Titans for the NFL’s worst. The Saints kept losses to the San Francisco 49ers and Arizona Cardinals to a single-score margin before suffering a 44-13 blowout to the Seattle Seahawks last Sunday.
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Pressed into action following Derek Carr’s offseason retirement, Spencer Rattler is averaging just 5.4 yards per pass attempt. Meanwhile, the defense has yielded a 118.9 quarterback rating with no interceptions.
Kellen Moore could stun Vegas and the NFL world by earning his first career victory this Sunday. Bettors should probably settle for the Saints covering the massive spread in a semi-competitive contest, or one with a timely garbage-time score for gamblers.
On the bright side, the Saints are actually 2.5-point favorites for an ensuing Week 5 home matchup against the New York Giants. The Bills are poised to also enter Week 5 as the biggest favorites, sporting an early 10-point cushion to take down the New England Patriots at Highmark Stadium.
This story was originally reported by The Spun on Sep 23, 2025, where it first appeared in the NFL section. Add The Spun as a Preferred Source by clicking here.