Garrard's scoring strike broke a 20-20 tie and helped boost the Jaguars (3-2) to the win, in which they got five field goals from Josh Scobee.
Garrard passed for 178 yards and three touchdowns, going 16-of-20 through the air with one interception. Two of his TD passes went to Marcedes Lewis.
Maurice Jones-Drew added 84 yards rushing for the victors.
Buffalo (0-5) dropped a fifth straight game to start a season for the first time since 1985.
Ryan Fitzpatrick led the Bills with three touchdown passes and 220 aerial yards.