Rahshon Clark chipped in with nine points and seven rebounds for the Cyclones (10-5), who lead by as much as 40 early in the second half en route to their seventh victory in eight games.
North Dakota (10-4) started just one player over 6-foot-5, and Iowa State's superior size and athleticism was apparent from the opening tip. The Cyclones shot 47.5 percent from the floor, forced 21 turnovers and outscored the Fighting Sioux 30-14 in the paint.
Travis Bledsoe and Emmanuel Little each scored 12 to lead North Dakota, which was playing its first game against a Division I opponent since losing to Kansas, 108-77, in 2002. The loss snapped a 10-game winning streak for the Fighting Sioux.
Iowa State took control with a 12-2 run to open the game, led by a pair of 3s from Bryan Petersen, and the rout was on. Wesley Johnson followed with two 3-pointers of his own as the Cyclones pushed their lead to 27-11 midway through the first half.
North Dakota made a brief surge, pulling within 29-18, but Iowa State reeled off 14 straight points to make it 43-18 with 2:41 left. The Cyclones led 48-22 at halftime.
It only got worse for the overmatched Fighting Sioux after the break. The Cyclones scored the first 14 points of the second half, a run capped by an Alex Thompson 3, to go up 62-22. North Dakota finally found some rhythm against Iowa State's reserves, cutting its deficit to 70-45 with 4:10 left.
Iowa State opens Big 12 action next Saturday at Baylor.