Villanova downed the Quakers for the 11th straight time, staying unbeaten in its opening seven games this year.
The Wildcats scored the game's first 11 points, grabbed an 18-point lead at halftime and easily held on despite shooting just 34 percent from the field.
JayVaughn Pinkston added 13 points for Villanova and Dylan Ennis had 11. Pennsylvania (2-5) was led by 17 points from Miles Jackson-Cartwright.
It was the first game for Villanova since the Wildcats posted impressive wins over Kansas and Iowa to win the championship of the Battle 4 Atlantis.