Buffalo Bills and San Francisco 49ers have played a total of 13 games against each other, including the regular season and playoffs. The Bills have won 7 of these games, while the 49ers have won 6 times. No games between the Bills and the 49ers ended in ties. The Bills and 49ers have yet to play a playoff game against each other.
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Buffalo Bills vs San Francisco 49ers Head To Head Records & Stats
| Event | Games | Buffalo Bills Won | San Francisco 49ers Won | Ties |
| NFL Regular Season | 13 | 7 | 6 | 0 |
| NFL Playoffs | 0 | 0 | 0 | 0 |
| Overall | 13 | 7 | 6 | 0 |
Buffalo Bills vs San Francisco 49ers H2H Longest Winning Streaks
The longest winning streak for the Buffalo Bills over the San Francisco 49ers is 2 games. The streak started on 16 October 2016 and ended on 7 December 2020. On the other hand, the longest winning streak for the San Francisco 49ers over the Buffalo Bills is 2 games. The streak started on 30 November 2008 and ended on 7 October 2012.
Buffalo Bills vs San Francisco 49ers: Last 10 Games Results
| Date | Home Team | Visiting Team | Winning Team | Final Score |
| 12/07/2020 | San Francisco 49ers | Buffalo Bills | Buffalo Bills | 24-34 |
| 10/16/2016 | Buffalo Bills | San Francisco 49ers | Buffalo Bills | 45-16 |
| 10/07/2012 | San Francisco 49ers | Buffalo Bills | San Francisco 49ers | 45-3 |
| 11/30/2008 | Buffalo Bills | San Francisco 49ers | San Francisco 49ers | 3-10 |
| 12/26/2004 | San Francisco 49ers | Buffalo Bills | Buffalo Bills | 7-41 |
| 12/02/2001 | San Francisco 49ers | Buffalo Bills | San Francisco 49ers | 35-0 |
| 10/04/1998 | Buffalo Bills | San Francisco 49ers | Buffalo Bills | 26-21 |
| 12/03/1995 | San Francisco 49ers | Buffalo Bills | San Francisco 49ers | 27-17 |
| 09/13/1992 | San Francisco 49ers | Buffalo Bills | Buffalo Bills | 31-34 |
| 12/17/1989 | San Francisco 49ers | Buffalo Bills | San Francisco 49ers | 21-10 |
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