Manziel, forced to sit out the first half of last week's season opener due to an NCAA infraction, returned to his Heisman Trophy form, completing 29-of-42 passes with three touchdowns and one interception.
Manziel also ran for a score before leaving late in the third quarter as the Aggies (2-0) cruised to the one-sided win.
Tra Carson scored twice on the ground and Mike Evans made seven catches for 155 yards for the victors.
Timothy Flanders run for 170 yards and two touchdowns on 19 carries for Sam Houston State (1-1).
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