The Saints and Bills have met nine times with New Orleans holding a 5-4 lead riding a three-game winning streak in the series. Although the Saints have a 2-3 record, they will be seeking their first win at the Superdome against Buffalo Sunday, with the two victories having taken place at Tulane Stadium and San Antonio's Alamodome. Three of the games have been decided by a touchdown or less, one by three points.
The teams first faced off in 1973, as the Saints recorded a 13-0 shutout, the first in club history. The teams did not meet again for seven years. This will be the first regular season meeting between the Saints and the Bills in the Superdome since 1998, as the 2005 contest was played at San Antonio's Alamodome due to Hurricane Katrina. A view of the results:
| Date | Result | Site | Attendance |
| 11/4/73 | W, 13-0 | Tulane Stadium | 74,770 |
| 9/21/80 | L, 26-35 | Superdome | 51,154 |
| 10/3/83 | L, 21-27 | Rich Stadium | 49,413 |
| 12/10/89 | W, 22-9 | Rich Stadium | 70,037 |
| 12/20/92 | L, 16-20 | Superdome | 68,591 |
| 12/27/98 | L, 33-45 | Superdome | 39,707 |
| 9/9/01 | W, 24-60 | Ralph Wilson Stadium | 71,447 |
| 10/2/05 | W, 19-7 | Alamodome | 56,688 |
| 9/27/09 | W, 27-7 | Ralph Wilson Stadium | 70,261 |
