Dante Cunningham and Dwayne Anderson each scored 25, and third-seeded Villanova rallied from a 14-point second-half deficit to top a tough American team, 80-67.
Corey Fisher netted 11 points for Villanova (27-7). The Cats ran off 15 straight points in the second half to go in front for good.
The 14th-seeded Eagles, Patriot League tourney champions, were primed to stun the Wildcats in essentially a home-game setting, but it didn't work out for American. Villanova went 24-of-26 from the foul line in the second half and finished the contest on a 33-12 run.
Garrison Carr scored 22, on 6-of-14 from beyond the arc, for American (24-8). The Eagles had a 13-game winning streak broken.
Brian Gilmore and Derrick Mercer each had 17 points for the Eagles.
Next up for Jay Wright's Nova team is the winner of the later game between sixth seed UCLA and No. 11 seed Virginia Commonwealth.