Chargers vs Bills NFL Picks and Predictions
Our Chargers vs Bills NFL picks and predictions break down every angle of this Week 3 matchup, from the point spread and moneyline to the total, injury report, and betting trends.
The Los Angeles Chargers travel to Buffalo in a Week 3 matchup against the 2-0 Bills. We break down the odds, matchup numbers, injuries, and betting trends to land on the best Chargers vs Bills pick. For the rest of the slate, check out our full Week 3 NFL Schedule with odds and predictions for every game.
You can explore all of this matchup data yourself with our sports betting research app, which we used to pull every stat in this breakdown. For our top touchdown scorer prop picks and DFS plays in this game, check out our Chargers vs Bills NFL Player Props and DFS Picks article.
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Chargers vs Bills Odds and Betting Lines
Buffalo is a 4.5-point home favorite, with the Chargers getting +7 at -110 and the Bills -7 at -110. On the moneyline, Los Angeles is priced at +300 while Buffalo sits at -308. The total for this game is 50.5, with the Over at +104 and the Under at -111.
Chargers vs Bills Matchup Breakdown
Over their last three games, the Chargers offense ranks 18th in rush-plus-receiving yards (302.8) against a Bills defense that ranks 10th in yards allowed in that category (282.4). Los Angeles ranks 13th in anytime touchdowns scored (2.0) against a Buffalo defense ranked 26th in anytime touchdowns allowed (2.8). Through the air, the Chargers rank 11th in passing yards (203.3) against a Bills defense ranked 17th in passing yards allowed (186.2), while on the ground Los Angeles ranks 13th in rushing yards (116.3) against a stingy Buffalo run defense ranked 7th in yards allowed (86.4). The Chargers rank 23rd in passing touchdowns (1.0) against a Bills defense ranked 31st in passing touchdowns allowed (2.2), while Los Angeles ranks 11th in rushing touchdowns (1.0) against a Buffalo defense ranked 11th in rushing touchdowns allowed (0.6).
At quarterback, Buffalo's Josh Allen carries a D matchup grade with projections of 233 passing yards, 1.8 passing touchdowns, and 0.3 interceptions, while Los Angeles' Justin Herbert carries a C+ matchup grade with projections of 189.4 passing yards, 1 passing touchdown, and 0.7 interceptions. Among the top skill players, Bills running back James Cook has a B matchup grade with projections of 102.5 total yards and 0.6 touchdowns, Chargers running back Omarion Hampton has a D+ matchup grade with projections of 54.8 total yards and 0.7 touchdowns, and Bills tight end Dalton Kincaid has a C matchup grade with projections of 57.4 total yards and 0.5 touchdowns.
Chargers vs Bills Injury Report
Los Angeles' injury report is led by receiver Ladd McConkey (ribs, Questionable, 9/17). Chargers receiver KeAndre Lambert-Smith (hamstring, Out, 9/15) is also out.
Buffalo's report is headlined by receiver DJ Moore (sprain, Questionable, 9/18) and running back Ty Johnson (hamstring, Questionable, 9/16). Bills receiver Tyrell Shavers (surgery, Out, 8/31) and receiver Skyler Bell (coach's decision, Out, 9/17) are also out, per HOF's injury data for this matchup.
Chargers vs Bills Betting Trends
Historically, Los Angeles has won straight-up in 58% of its games and covered the spread in 68% of its games, while Buffalo has won straight-up in 71% of its games and covered in 52% of its games, based on HOF's trend data. The total trend stands out here: games involving the Chargers have gone Under 84% of the time and Over just 16% of the time, while games involving the Bills have gone Under 57% of the time and Over 43% of the time.
Our Pick: Chargers vs Bills
Our pick for this game is the Under 50.5. Games involving the Chargers have stayed Under the total in 84% of games, and Bills games have leaned Under as well at 57%. Buffalo also has one of the better run defenses in the league at 7th in rushing yards allowed, and neither offense grades out as explosive through the air in this matchup, with Justin Herbert's C+ grade being the best of the two starting quarterbacks. Pick: Under 50.5.
For player-specific plays in this game, see our Chargers vs Bills touchdown scorer picks, where we single out two players who are set up to find the end zone.
How We Made Our Chargers vs Bills NFL Picks and Predictions
Our Chargers vs Bills NFL picks and predictions are built directly from HOF's sports betting research app rather than gut feel or outside commentary. For every Week 3 matchup, we start with HOF's live point spread, moneyline, and total, then layer in the team grades HOF assigns across offense and defense to see where a real statistical edge exists. From there, we cross-reference HOF's injury report to confirm which players are active, questionable, or out, since a single absence can shift a matchup grade significantly.
We also check HOF's betting trends data — how each team has performed against the spread and the total recently — to see whether the market is lining up with or against the statistical picture. Only after weighing the odds, the matchup grades, the injury report, and the betting trends together do we land on the spread, moneyline, or total pick we publish here. We don't publish a pick without a clear data-backed reason behind it, and we update our numbers as HOF's app updates its own lines and grades throughout the week.