San Francisco 49ers vs. Buffalo Bills: Picks, Predictions, Odds and Player Props

Week 13's Sunday slate concludes with with a cross-conference matchup between the struggling San Francisco 49ers and the high-flying Buffalo Bills.

This game is scheduled for Sunday, December 1st at 8:20 PM ET and will be played at Highmark Stadium in Orchard Park, New York. This Sunday night contest will also be broadcast on NBC and can be streamed through Peacock.

Here, we'll preview this game between the 49ers and Bills and will provide you with our two best bets for this game.

San Francisco 49ers vs. Buffalo Bills betting picks and predictions

Buffalo Bills -7.0 (-105)

Our first prediction for the game between the Bills and 49ers targets Buffalo to win this game by more than a touchdown.

The Bills enter this game with a record of 9-2 and are currently considered one of the best teams in the NFL. Following a win against the Kansas City Chiefs in Week 11, the Bills have opened up a four-game lead in the AFC East. 

The Bills have one of the best offenses in the league as well, averaging 29.1 points per game while allowing 19.5 points per game.

Quarterback Josh Allen is having another fantastic season, having thrown for 2,543 yards so far, with 18 touchdowns and five interceptions. He's also rushed 67 times for 316 yards and five TDs.

Running back James Cook is the top rusher on the Bills, having rushed for 596 yards and he has scored 10 touchdowns, the fourth most in the league this season. 

On the other side are the 49ers, who enter this game with a record of 5-6.

They are coming off a blowout defeat to the Green Bay Packers in Week 12 as they lost by a score of 38-10.

Admittedly, the 49ers have had a ton of injuries this year, including quarterback, Brock Purdy. He missed the game last week with a shoulder injury and is now questionable for this game. 

On paper, this game looks to be a complete mismatch and the weather could certainly play a major factor here.

With Purdy still questionable and likely not at 100% even if he does play, backing the Bills to cover the touchdown spread on Sunday night is our best bet. 

James Cook Anytime Touchdown (-120)

Our second prediction for this game focuses on James Cook scoring a touchdown at any time. As mentioned above, Cook has 10 rushing touchdowns this season, plus, he also has one receiving touchdown.

He has scored at least one touchdown in five of the last six games, including two last week against the Chiefs.

Because Cook has become one of the best offensive weapons for the Bills this season, backing him to score a touchdown at anytime is our second-best bet.

Read more betting picks and predictions for the NFL on site.

San Francisco 49ers vs. Buffalo Bills odds

San Francisco 49ers	+255 ML
Buffalo Bills	-315 ML
Spread	BUF Bills -7.0
Total Points	O/U 44.5

San Francisco 49ers vs. Buffalo Bills player props

Anytime Touchdown

Christian McCaffrey (SF 49ers)	-138
James Cook (BUF Bills)	-120
Josh Allen (BUF Bills)	+120
Amari Cooper (BUF Bills)	+162
Khalil Shakir (BUF Bills)	+162
Dalton Kincaid (BUF Bills)	+162

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This article was written by a partner sports writer via Spotlight Sports Group. All odds displayed on this page were correct at the time of writing and are subject to withdrawal or change at any time.