Adam Dingwell added two touchdown passes as San Diego State secured at least a share of the Mountain West Conference title, which is its 19th overall and first since 1998.
The Aztecs (9-3, 7-1 Mountain West) also won their seventh straight and posted their first nine-win regular season since 1977.
San Diego State gained 564 yards total offense, including 400 on the ground.
Wyoming (4-8, 3-5) saw its three-game win streak stopped.
The Cowboys were led by Brett Smith who passed for 260 yards and two TDs, despite being sacked six times. Smith also rushed for 35 yards and two scores.
Robert Herron caught nine of Smith's passes for 187 yards and hauled in both TDs - one for 70 yards and the other 42 yards.