An early fumble by CJ Spiller set the Patriots up deep in Bills territory and Tom Brady found Julian Edelman in the back of the end zone for the first score of the game.
The game turned into a defensive struggle until Stevan Ridley's second fumble of the game was returned for a touchdown to cut the Patriots lead to 10-7 in the second quarter. The Pats answered on the next drive as Brady again found Julian Edelman for his second touchdown of the day.
A Brady interception before halftime led to an 18-yard touchdown from EJ Manuel to Robert Woods.
Buffalo continued its momentum with a touchdown drive to open the third quarter, but the Patriots would hold them scoreless from there on out.
Stephen Gostkowski nailed two fourth quarter field goals, including one from 35 yards with five seconds left to give New England the win.
The Bills' 10 penalties were a huge factor and mistakes in the fourth quarter cost them, as they were unable to put the Patriots away.
It was a sloppy game, as opening weekend games often are, and the Pats will have to turn the page quickly as they host the Jets on Thursday night.