by Rod Pearson
Tuesday, Sep 22, 2026
Game Time: 1:00 pm ET, Sunday, September 27, 2026
Venue: Highmark Stadium, Orchard Park, NY
Where to Watch: FOX
Opening Odds at USA Sportsbooks
DraftKings: Point Spread: Chargers +7, Bills -7; Over/Under: 50.5 points
Bet365: Point Spread: Chargers +7, Bills -7; Over/Under: 50.5 points
BetMGM: Point Spread: Chargers +7, Bills -7; Over/Under: 50 points
Season Record
Los Angeles Chargers: 0-2 (4th place, AFC West)
Buffalo Bills: 2-0 (1st place, AFC East)
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Recent Form
Los Angeles Chargers: lost their last game at home against the Las Vegas Raiders 26-14.
Buffalo Bills: won their last game at home against the Detroit Lions 41-31.
Los Angeles Chargers vs Buffalo Bills Preview and Analysis
The Chargers are entering this game with a 0-2 record overall and they have a 0-1 record in their divisional games too. They are 0-2 in their home games, 0-0 in their road games, and they are also 0-0 in their neutral site games this season, but they will be on the road for this game. They lost their last game against the Las Vegas Raiders 26-14. Kirk Cousins was the starting QB and he completed 19/29 passes for 253 passing yards, 3 touchdowns, and 1 interception. Ashton Jeanty led the team in rushing yards with 48. Tre Tucker led the receivers with 119 receiving yards on 5 receptions and 1 TD. Quay Walker and Nakobe Dean each led the defense in that game with 10 solo tackles while Malcolm Koonce led the defense in sacks with 1. Hezekiah Masses came away with 2 interceptions for them in that one.
The Bills are entering this game with a 2-0 record overall and they have a 0-0 record in their divisional games too. They are 1-0 in their home games, 1-0 in their road games, and they are also 0-0 in their neutral site games this season, but they will be at home for this game. They won their last game against the Detroit Lions 41-31. Josh Allen was the starting QB and he completed 20/31 passes for 248 passing yards, 3 touchdowns, and 0 interceptions. James Cook led the team in rushing yards with 135 and 1 TD. Dalton Kincaid led the receivers with 95 receiving yards on 7 receptions and 1 TD. Christian Benford led the defense in that game with 8 solo tackles while Greg Rousseau led the defense in sacks with 2. No one on the defense came away with an interception for them in that one.
Chargers vs Bills Prediction
The current betting odds have the Bills listed as a 7 point favorite in this game according to Draftkings Sportsbook. The Bills have looked great in their games this season with their 2-0 record overall which has them right at the top of the AFC East. They have looked great on their home field too with their 1-0 home record this season. Meanwhile, the Chargers have looked terrible in their games this season with their 0-2 record overall which has them right at the bottom of the AFC West. They haven't played any road games yet and will be playing their 1st road game of the season here. The Chargers are coming off a 26-14 loss to the Raiders in their last one and that was right after losing to the Cardinals in week 1 by the same score. This is a team that had Super Bowl aspirations coming into the season and they have opened the season with losses against 2 of the worst teams in the NFL last year. The defense hasn't looked terrible for them, but the offense has and they have had a lot of trouble trying to put up points against worse defenses. The Bills are coming off a 41-31 win over the Lions in their last one and they played on Thursday night, so they have some extra days to prepare for this game. They have looked like one of the best teams in the NFL in their 2 games this year and their offense has been rolling with over 30 points scored in both games this season. The defense hasn't looked great, giving up over 30 points in both games this year, but they have definitely improved from last season and have been making big impact plays when the Bills need it most. The offense has looked unstoppable with Josh Allen already playing at a high level, so look for them to roll over this struggling Chargers team that has been a mess offensively. The best way to place a bet here is on the Bills to cover the spread in this game.
Chargers Bills Prediction: Our NFL Pick for Sunday, September 27, 2026 (1:00 pm ET start time) is Bills 34 Chargers 20.
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NFL Betting Trends
Los Angeles Chargers: 32-44 ATS against AFC East division opponents. 44-63 ATS off a loss against a division rival. 19-9 OVER off an upset loss to a division rival as a favorite. 34-23 OVER on the road after scoring 14 points or less last game.
Buffalo Bills: 65-47 ATS after allowing 30 points or more last game. 67-48 ATS in September games. 11-6 ATS at home in all games where the total is greater than or equal to 49.5. 44-31 OVER against AFC West division opponents. 30-21 OVER at home off a home win.
Key Injuries
Los Angeles Chargers: B. Dupree (LB) Injured - Rest. D. Davis (WR) Injured - Calf. K. Mack (LB) Injured - Rest. D. Leonard (CB) Questionable - Abdomen. L. McConkey (WR) Questionable - Rib. A. Mesidor (LB) Injured - Calf. E. Molden (CB) Out - Hamstring. T. Pipkins III (OT) Out - Knee. T. Tart (DL) Injured - Ankle. D. Tomlinson (DL) Injured - Hamstring.
Buffalo Bills: E. Oliver (DL) Out - Hip. C. Bishop (S) Questionable - Knee. B. Chubb (LB) Injured - Thumb. T. Bernard (LB) Injured - Calf. T. Johnson (RB) Questionable - Hamstring. T. Sanders (DL) Questionable - Knee. J. Hancock (CB) Injured - Quad.
Notable Quotes
“The fight was there. We’re losing in the margins. That’s what we have to get fixed.” - Jim Harbaugh after his team’s loss against the Raiders in their last game.
“I wanted us to take the ball in this environment and set the tone. That was the start that we needed.” - Joe Brady after his team’s win against the Lions in their last game.
Starting Lineups
Los Angeles Chargers
WR Johnston, Quentin
WR Harris, Tre'
WR McConkey, Ladd
TE Kolar, Charlie
QB Herbert, Justin
RB Hampton, Omarion
FB Ingold, Alec
Buffalo Bills
WR Coleman, Keon
WR Moore, DJ
WR Shakir, Khalil
TE Kincaid, Dalton
QB Allen, Josh
RB Cook III, James
Statistical Leaders
Los Angeles Chargers
Passing: Justin Herbert (401)
Rushing: Omarion Hampton (137)
Receiving: Ladd McConkey (117)
Touchdowns: Omarion Hampton (2)
Buffalo Bills
Passing: Josh Allen (582)
Rushing: James Cook III (192)
Receiving: Dalton Kincaid (225)
Touchdowns: Josh Allen (4)
Coaches:
Los Angeles Chargers: Jim Harbaugh (3rd season)
Buffalo Bills: Joe Brady (1st season)
Rod Pearson
About the Author:
Rod Pearson has been a rabid sports fan his entire life. He grew up in Ontario, and was skilled in both hockey and baseball, and pitched in an elite baseball league for many years. In 2022, Rod decided to hang up his glove, so that he could write about the sports he loves -- but from a gambling perspective. Join Rod every day as he breaks down the games to find the best betting value.
