The game begins at 4:25 p.m. EDT and will be shown by FOX, or watch a live stream online by purchasing NFL Sunday Ticket Max.
San Francisco recovered from their disappointing Week Three loss by throttling the New York Jets for a 34-0 road victory last week, and have outscored opponents 104-65 this season.
The 49ers created four New York turnovers, including a 51-yard fumble return by cornerback Carlos Rogers, and held the Jets to 145 total yards, and rushed for 245 yards and three touchdowns.
Running back Frank Gore recorded 62 yards on 21 attempts, and quarterback Alex Smith was a steady 12-for-21 for 143 yards.
San Francisco now takes on a Buffalo team that squandered a 14-point lead and lost 52-28 to the New England Patriots.
Buffalo gave up six straight touchdowns in the second half, and 580 total yards, after opening up a 21-7 lead in the third quarter off a 68-yard touchdown catch by receiver Donald Jones.
Quarterback Ryan Fitzpatrick threw four interceptions on the day, including two in the fourth quarter while the Bills attempted a comeback. He would finish 22-for-39 for 350 yards and four touchdown passes.
Last Sunday was the first game of the season for the Bills to record less than 100 yards rushing, with running back C.J. Spiller leading Buffalo with 33 yards on the ground.
The Bills splurged in free agency on defensive end Mario Williams, but the results have been inconsistent at best. Buffalo’s defense is still near the bottom of the NFL, ranking 23rd in passing and 28th in rushing defense.
Betting Odds: San Francisco is favored by 10 points; Over/Under: 44.5 points
Prediction: Fitzpatrick must avoid forcing his passes if the Bills are down early or San Francisco will capitalize and pick him off. San Francisco will continue to run the ball and play top notch defense in a winning effort.
Predicted Score: San Francisco 24, Buffalo 17