Saints vs Bills Prediction 9/28/2025 Today’s NFL Picks

In this article we will formulate a Saints vs Bills prediction for this NFL game on Sunday, September 28th at Highmark Stadium in Orchard Park, New York. Let’s take a look at the prediction for this week 4 matchup.

New Orleans Saints Betting Preview

The New Orleans Saints are 0-3 this year after they lost to Seattle by a score of 44-13 in their last game. New Orleans trailed 21-0 after the first quarter and 38-6 at halftime, but did win the second half by a total of 7-6 in the blowout loss. The Saints were out gained by a total of 320-284, went 5-15 on third downs, and tied the turnover battle at one in the game. Spencer Rattler went 28-39 for 218 yards, one touchdown, and one interception, while Alvin Kamara rushed 18 times for 42 yards. Chris Olave led the receivers with 10 catches for 57 yards in the game. The NO defense recoded zero sacks and three tackles for loss in the defeat. 

New Orleans lost their first game by a score of 20-13 against the Cardinals and their second game by a score of 26-21 against the 49ers. The Saints are averaging 15.7 points per game with 199.7 passing yards and 102.3 rushing yards per game, while they are allowing 30 points against per game this season. Spencer Rattler has completed 67.2% of his passes for 639 yards, four touchdowns, and one interception, while Juwan Johnson has caught 19 passes for 176 yards and one score. Alvin Kamara has led the rushing attack with 186 yards and one touchdown on 50 carries this year. 

Buffalo Bills Betting Preview

The Buffalo Bills are 3-0 this season after they defeated Miami by a score of 31-21 last week. Buffalo was tied at seven after the first quarter and tied at 14 at the half, but did score 17 points in the second half to pull away with the win. The Bills out gained Miami by a total of 360-276, went 6-11 on third downs, and won the turnover battle by a margin of 1-0 in the game. Josh Allen went 22-28 for 213 yards and three touchdowns, while James Cook rushed 19 times for 108 yards and one score. Dalton Kincaid was the leading receiver with five catches for 66 yards and one touchdown in the win. The Buffalo defense recorded zero sacks and five tackles for loss in the game. 

Buffalo also has wins over the Ravens and Jets by scores of 41-40 and 30-10 to start the season. The Bills are averaging 34.0 points per game with 257.0 passing yards and 163.0 rushing yards per game, while they are allowing 23.7 points against per game this season. Josh Allen has completed 69.7% of his passes for 755 yards and five touchdowns, while Keon Coleman has caught 14 passes for 158 yards and one score. The leading rusher for the Bills is James Cook, who has 284 yards and four touchdowns on 53 carries this season. 

Why the Saints will cover

The Saints have won each of their last six Week 4 games against AFC opponents.
The Saints have covered the spread in 14 of their last 15 games played as underdogs on the East Coast.
The Bills have failed to cover the spread in six of their last eight games as home favorites against NFC opponents.
The Bills have lost the first quarter in each of their last three Week 4 home games against NFC opponents.
The Bills have lost the first half in six of their last seven Week 4 games against NFC opponents.

Total Points Facts

Each of the Bills’ last seven September games at Highmark Stadium have gone OVER the total points line.
Each of the Saints’ last five games against AFC East opponents have gone UNDER the total points line.

Buffalo Bills Player Prop Facts

Josh Allen has scored two or more touchdowns in each of the Bills’ last three games against NFC opponents.
James Cook has scored at least one touchdown in each of the Bills’ last seven games against teams with a losing record.
Josh Allen has recorded 263+ passing yards in eight of the Bills’ last 10 September games at Highmark Stadium.
Curtis Samuel has recorded 19+ receiving yards in seven of his last eight appearances with his team as a favorite against NFC South opponents.
Josh Allen has recorded 41+ rushing yards in four of the Bills’ last five games against NFC South opponents.
Curtis Samuel has recorded 32+ rushing and receiving yards in eight of his last nine September appearances against NFC opponents.
Josh Allen has recorded 22+ completions in nine of the Bills’ last 10 September games at Highmark Stadium.
Heading into Week 4, James Cook ranks T1st in the NFL in rushing touchdowns (4) this season.

New Orleans Saints Player Prop Facts

Brandin Cooks has scored a touchdown in five of his last six road appearances against AFC opponents.
Spencer Rattler has recorded 207+ passing yards in each of the Saints’ last five games as underdogs.
Brandin Cooks has recorded 19+ receiving yards in each of his 22 previous regular season appearances with the Saints as underdogs.
Alvin Kamara has recorded 59+ rushing yards in five of the Saints’ last six road games against AFC opponents.
Brandin Cooks has recorded 19+ rushing and receiving yards in each of his 22 previous regular season appearances with the Saints as underdogs.
Spencer Rattler has recorded 25+ completions in each of the Saints’ last four games as underdogs.
Heading into Week 4, Chris Olave leads the league for targets (37) this season.

Matchup/League Facts

Bills – four different players have recorded 60+ receiving yards in a game this season – equal-most in the NFL, heading into Week 4.
Heading into Week 4, the Bills rank 1st in the NFL in yards per game (420.0) this season.
Heading into Week 4, the Saints rank 32nd in the NFL in Q2 opponent points per game (13.7) this season.
Heading into Week 4, the Saints rank 32nd in the NFL in H1 opponent points per game (23.7) this season.

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Saints vs Bills Prediction 

New Orleans comes into this matchup looking to bounce back after getting blown out in their last game, but they will be on the road against a very good Buffalo team here. The Bills are 3-0 to start the year and they have scored at least 30 points in all three games. I expect Buffalo to have another big day on offense, as the Saints have allowed 70 points in their last two games, but I am taking the Saints here. New Orleans was competitive in their first two games and this is a huge number to cover, so give me the Saints to keep it somewhat close.