The Cardinals remained unbeaten in four games and moved into the tournament semifinals for a date with No. 14 Missouri on Friday.
Louisville grabbed a six-point halftime lead, then went on a 14-2 run during the first 10 minutes of the second period.
Northern Iowa, however, fought back to within 48-46 when Jake Koch made two free throws with 43 seconds remaining.
Peyton Silva attempted a jumper for Louisville with the shot clock running down and when it failed to go Smith was there for the rebound. His rebound turned into a layup and he was fouled on the play by Anthony Jones.
The ensuing free throw gave Smith 16 points for the game and he was the only Louisville player in double figures.
Marc Sonnen led Northern Iowa (3-1) with 11 points.
Louisville won despite hitting just 30 percent of its field goal attempts. The Cardinals also had 20 turnovers.