Shonn Greene contributed 117 yards on the ground and Mark Sanchez completed 14-of-24 passes for 161 yards with a pair of touchdowns for the Jets (3-1), who posted their third straight win against AFC East opponents.
New York unleashed a potent offense that rolled up 273 rushing yards.
Leading only 17-7 at the half, the Jets put up 21 third-quarter points to turn the game into a rout. Dustin Keller hauled down two touchdown receptions in 90-second span during the outburst.
Ryan Fitzpatrick had a tough day for Buffalo (0-4), going 12-of-27 passing for just 128 yards with two touchdowns. He also gained 74 rushing yards on seven carries.
The Bills have posted their first 0-4 start since 2004.