Bills vs. Saints Game Preview: Top storyline, odds, player to watch & prediction

After dispatching three straight conference opponents, the Buffalo Bills will encounter their first NFC opponent of the year on Sunday at 1 p.m. at Highmark Stadium.

Buffalo welcomes the hapless 0-3 New Orleans Saints to town, with its non-conference foe in desperate need of what would be an improbable victory.

New Orleans was embarrassed by the Seattle Seahawks in a 44-13 defeat last week and will be looking to rebound. However, unfortunately for the Saints, they’ve traveled over 1,000 miles only to run into a Super Bowl contender that has proven to be one of the best teams in football through three regular-season games.

Game day is fast approaching. Let’s dive into the news and a few notes surrounding this Week 4 tilt.

What’s Vegas Saying?

As of Saturday morning, the Bills were sizable 15.5-point favorites to beat the Saints, down a point from where the point spread opened, at 16.5, per FanDuel. But that number is now down to 14.5 as of early Suday morning.

Game odds refresh periodically and are subject to change. If you or someone you know has a gambling problem and wants help, call 1-800-GAMBLER.

Weather Report

It is expected to be another beautiful day for football when the Bills and Saints take the field on Sunday. The forecast calls for early-morning showers that will give way to clear skies, with temperatures approaching 80 degrees and winds around 5 mph by kickoff.

Sep 14, 2025; East Rutherford, New Jersey, USA; Buffalo Bills running back James Cook (4) reacts after rushing the ball for a touchdown | Vincent Carchietta-Imagn Images

Bills’ Injuries

Buffalo has declared two players as questionable to play vs. the Saints, while two others will remain out.

Defensive tackle Ed Oliver (ankle) and linebacker Matt Milano (pectoral) have each missed multiple games with their respective ailments and will once again be sidelined in Week 4.

Oliver has been out since his foot was stepped on during practice leading into a Week 2 matchup with the New York Jets. He initially was placed in a walking boot and was seen by reporters using a medical scooter to get around. He has since ditched the boot and scooter, but was still walking with a noticeable limp in videos posted to social media this week.

Milano’s injury has been a bit more dubious, as he was removed from the Bills’ win over the Jets at halftime and has since been held out of practice and game action. Head Coach Sean McDermott said he was still uncertain if either Milano or Oliver would be able to suit up for Buffalo in Week 5 against the New England Patriots.

Offensive lineman Spencer Brown (calf) and edge rusher A.J. Epenesa (pectoral) are the two players who are questionable to play this weekend.

Brown sustained his injury during the team’s Week 3 win over the Miami Dolphins, but still wound up playing 100% of the team’s offensive snaps. He was held out of practice to begin the week but was upgraded to a limited participant on Friday. Epenesa was injured during Wednesday’s practice and has been limited throughout the week.

If Brown cannot play, Ryan Van Demark would likely take over at right tackle, while Javon Solomon would likely be in line to replace Epenesa in the defensive line rotation if the veteran edge rusher cannot go. Rookie Landon Jackson may also earn a game-day jersey for the first time this season if Epenesa is out on Sunday due to injury.

Saints’ Injuries

The Saints will be without one of their top pass rushers against the Bills, as, for the third straight game, Chase Young is out due to a calf injury sustained during training camp.

Young was an important piece for New Orleans’ defense a season ago, playing in all 17 games for the first time in his career. During the 2024 campaign, Young recorded a career-high quarterback pressure rate of 16.2% while finishing with 5.5 sacks. Without him, the Saints have posted the lowest QB pressure rate in the league through three games, a mark of 21.6%.

Elsewhere on the Saints’ injury report, offensive lineman Dillon Radunz is out with a toe injury, while wide receiver Devaughn Vele is questionable to play with a hip injury.

Radunz started the first two games of the season for the Saints, who will get two starters along their OL — Taliese Fuaga and Trevor Penning — in Week 4. Vele, who has recorded two receptions for 16 yards this season, was limited throughout the week. Vele has played 20% of the special teams snaps for New Orleans this season.

Coaching Matchup

For the second time in three weeks, the Bills will face off with a neophyte head coach, as New Orleans’ Kellen Moore is currently winless in his first season with the team. Moore previously served as the Dallas Cowboys’ offensive coordinator from 2019 to 2022 before moving to the Los Angeles Chargers, assuming the same role during the 2023 campaign. Last season, Moore was in Philadelphia, calling the plays for the Eagles en route to their win in Super Bowl LIX.

The Eagles finished last season eighth in total yards per game (367.2) and seventh in points per game (27.2). So far this season, New Orleans has scored just 15.7 points per game, the fourth-fewest in the NFL.

McDermott improved his record as Bills head coach to 96-52 this past week, which equates to a career winning percentage of 0.649, which is tied with Green Bay Packers head coach Matt LaFleur for fourth-best among active head coaches. The Jacksonville Jaguars’ Liam Coen sits above McDermott with a 0.667 winning percentage, but has coached just three games in his first season as a head coach.

The Bills’ head coach is 1-1 against the Saints in his career, with the latest matchup resulting in a 31-6 Bills’ win in Week 12 of the 2021 season.

Top Storyline

There hasn’t been much to complain about when it comes to the Bills’ performance through the first three weeks of the season. The offense has been clicking, and the defense has done enough to help Buffalo earn three straight wins to begin the year.

With that said, the Bills have faced a few bumps in the road defensively, particularly a week ago when Buffalo allowed Miami to convert 66.7% of its third-down opportunities. Going up against a Saints’ offense that has struggled to put up points this season, this week has the makings of a get-right game for the Bills’ defense.

New Orleans comes equipped with a second-year quarterback, Spencer Rattler, who is surrounded by a few quality skill players, including running back Alvin Kamara and wide receiver Chris Olave. Both Kamara and Olave will attract plenty of attention on Sunday.

It’s been a slow go for the entire Saints’ offense to begin the year, including Kamara, who is averaging just 3.7 yards per attempt and has totaled just nine receptions for 47 yards through three games. Olave has also struggled to get going, recording just 7.2 yards per reception over the first three weeks.

Sep 21, 2025; Seattle, Washington, USA; New Orleans Saints running back Alvin Kamara (41) runs the ball during the first quarter against the Seattle Seahawks | Joe Nicholson-Imagn Images

If New Orleans is to have any chance to pull off an improbable upset, the Saints’ road to victory would start with getting Kamara and Olave involved more successfully than they’ve been able to over the first three weeks of the season.

Buffalo remains without one of its best defenders in space, Milano, which will force Dorian Williams into a starting role for the second straight week. Williams’ ability to chase down Kamara out of the backfield will play a significant role in the Bills’ defense’s ability to find success against the Saints’ attack.

In addition, Tre’Davious White will once again be tested at the cornerback position, as he was a week ago against the Dolphins’ speedy pass catchers. White has found varying success in coverage since coming back from a groin injury that kept him sidelined in Week 1. Through two starts, he has allowed five receptions for 33 yards and a touchdown while being targeted eight times.

Nobody is saying that this Saints’ offense is a sleeping giant, or anywhere near that. But Kamara and Olave are a talented twosome that must be accounted for this week.

Player to Watch

Edge rusher Joey Bosa has been on the field a ton through the first three games with his new team this season. During Weeks 1-3, Bosa played 72% of the snaps, which was a far higher snap share than the oft-injured was projected to garner in his first season in Buffalo. The eight-year veteran has been forced into action a bit more than anticipated out of necessity and has performed well, recording a quarterback pressure rate of 18.6% and coming away with a league-high three forced fumbles through three weeks.

With that said, it’s about time the Bills scale things back with the 30-year-old, or it may be a matter of time before we see him sidelined. In this game against the Saints, QB Josh Allen and the Buffalo offense should be able to jump out in front with an early lead. New Orleans allowed the Seahawks to score touchdowns on their first four drives, while Seattle recorded at least a field goal on seven consecutive possessions a week ago.

If the Bills’ attack can get rolling immediately, that would allow Buffalo to contemplate resting Bosa and other veteran players throughout the second half. If all goes well, Bosa should see nowhere near the high number of snaps he saw a week ago.

Prediction — Bills 35, Saints 10

This should be an easy win for the Bills. After allowing the Dolphins to hang around in Week 3, I'm expecting Buffalo to power through New Orleans, performing dominantly from pillar to post. Not much else to say here.

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