The San Francisco 49ers (5-6) and Buffalo Bills (9-2) face off on Sunday Night Football. Kickoff is set for in 8:20 p.m. ET from Highmark Stadium in Orchard Park, N.Y. The game will be broadcast on NBC and can be streamed on Peacock or YouTube TV.
49ers vs Bills odds (via DraftKings) have the Bills as -310 moneyline favorites and 49ers as +250 underdogs. The over/under is 45 points (-110/-110). The Bills are 6.5-point favorites on the spread over the 49ers (-6.5; -120).
Once again, the 49ers will be without star linemen on both sides of the ball in Nick Bosa and Trent Williams. However, quarterback Brock Purdy is active after missing last week's game.
Let's get into my 49ers vs Bills predictions and NFL picks — plus the latest betting trends, injuries, inactives, weather forecast and more.
49ers vs Bills Odds, Spread, Over/Under, Best Bet
| San Francisco 49ers Odds | ||
|---|---|---|
| Spread | Over/Under | Moneyline |
+6.5 +100 | 45 -110o / -110u | +250 |
| Buffalo Bills Odds | ||
|---|---|---|
| Spread | Over/Under | Moneyline |
-6.5 -120 | 45 -110o / -110u | -310 |
- 49ers vs Bills spread: 49ers +6.5 (+100), Bills -6.5 (-120)
- 49ers vs Bills over/under: 45 (-110o / -110u)
- 49ers vs Bills moneyline: 49ers +250, Bills -310
- 49ers vs Bills best bet: Under 45 (Bet to Under 43.5)
My49ers vs Bills pick is on the game total to go under 45. For all of your NFL bets, be sure to find the best lines by using our live NFL odds page.
49ers vs Bills Predictions
Spread
No play.
The 49ers are shorthanded but desperate, which makes it a tough spot to lay nearly a TD with Buffalo.
Moneyline
No play.
I'd lean toward a Bills victory coming off the bye against a short-handed 49ers team, but the 49ers will be desperate after back-to-back losses.
I don't see value in laying in the range of -250.
Over/Under
I like the under in what should be below-freezing temps with wind and potential snow.
The best line available is 44.5 (-110) at BetMGM, Caesars Sportsbook and bet365.
My Pick: Under 45 (to 43.5)
49ers vs Bills Preview, Prediction — Sunday Night Football
The 49ers are battling not just the Bills, but attrition.
Offensively, quarterback Brock Purdy is dealing with shoulder soreness, but he is expected to return after a one-game absence — that's the good news.
The bad news: Left tackle Trent Williams (ankle) is expected to miss his second straight game.
In two games without Williams last season, Purdy went 0-2 while throwing for just two TDs and four interceptions. The 49ers scored 17 points in both of those contests.
Christian McCaffrey averaged only 3.67 yards per carry in those matchups, and struggled last week without Williams, rushing 11 times for 31 yards (2.82 YPC).
Given the weather, Purdy's health, and the ineffectiveness of Deebo Samuel sans Brandon Aiyuk (IR-knee), I expect head coach Kyle Shanahan to come out with a run-heavy game plan that also features McCaffrey extensively in the quick passing game.
Defensively, the 49ers allowed a season-high 38 points last week without edge rusher Nick Bosa, who will be unable to return and make this defense great again after missing the entire week of practice with hip and oblique injuries.
The 49ers defense did play better than the final score looked, however, holding the Packers to a respectable 4.0 YPC (42-169) and 7.1 YPA (23-163).
It's tough to know exactly where the Bills are in terms of their downfield passing game coming out of the bye.
Tight end Dalton Kincaid (knee) is out and Keon Coleman (wrist) was limited in practice all week and is listed as questionable after missing nearly a month. Amari Cooper is off the injury report but has yet to assume a full-time role.
The constant in the Bills' passing game has been slot receiver Khalil Shakir (56 receptions, 599 yards, two TDs on 66 targets), who is likely to again bust out against a 49ers defense also missing slot corner Deommodore Lenoir (knee).
The kicking game could also factor in here with 14 mph winds in the forecast.
Buffalo's Tyler Bass has been average in terms of field-goal percentage (84.6%, 16th), but he has missed four extra points and ranks second-to-last in extra-point percentage (89.2%).
San Francisco's Jake Moody hasn't missed a PAT yet, but ranks 23rd in field-goal percentage (81.8%).
Per our Action Labs data, the under is 60-38 (61.2%) when the temperature is freezing or below over the past decade, covering by 1.8 points per game.
My Pick: Under 45
49ers vs Bills Betting Trends
- 91% of bets and 89% of the money are on the Bills moneyline
- 83% of bets and 54% of the money are on the over
- 60% of bets and 73% of the money are on the Bills to cover the spread
49ers vs Bills Inactives
49ers Inactives
- OL Trent Williams
- OL Aaron Banks
- DL Jordan Elliott
- DL Nick Bosa
- CB Deommodore Lenoir
- LB Demetrius Flannigan-Fowles
- QB Brandon Allen
Bills Inactives
- WR Keon Coleman
- CB Kaiir Elam
- LB Edefuan Ulofoshio
- DE Javon Solomon
- C/G Will Clapp
- TE Dalton Kincaid
- QB Mike White
