The key score with 9:23 left in the game lifted the Jets (2-1) to a victory despite being whistled for 163 team penalty yards.
Smith fired two touchdowns in all and added a rushing score, completing 16-of-29 passes for 331 yards with a pair of interceptions.
Holmes ended with five catches for 154 yards, while Stephen Hill hauled down three passes for 108 yards and a long touchdown for New York.
The Bills' EJ Manuel was sacked eight times. The rookie completed just 19-of-42 passes for 243 yards and a touchdown.
Dan Carpenter kicked four field goals for Buffalo (1-2).