Leading 15-10, Villanova (3-1) then turned it over to its defense. James Pitts intercepted Billy Ragone's pass on the Quakers' next possession and returned it 56 yards for the final margin.
Penn (1-1) then started at the Villanova 41 after Aaron Bailey's 46-yard kickoff return and it reached the 25 before losing the ball on downs.
Villanova, the defending Football Championship Subdivision champion, trailed 7-0 early in the second quarter but came back with a safety less than two minutes later when a bad snap sailed into the end zone.
After the ensuing free kick started it at the Penn 42, Villanova took a 9-7 lead into halftime on Angelo Babbaro's 1-yard touchdown run.