Penn fell behind early and never recovered as the Quakers lost their first game of the season to Duke at Cameron Indoor Stadium, 66-50, on Friday afternoon.
Penn trailed at the half by 16, but played the Blue Devils evenly after intermission.
Leaonna Odom led the way for Duke with a game-high 23 points and 16 rebounds. Haley Gorecki followed with 12 points and 10 assists.
Freshman guard Kayla Padilla paced the Quakers with 15 points. Sophomore forward Kennedy Suttle added 11 points.
Penn (4-1) will host Hartford on Monday at the Palestra at 7 p.m.