The Quakers led by 41-39 at halftime, but the Patriots quickly gained the lead in the opening minutes of the second half on a basket and free throw by guard Bryon Allen. They did not trail for the rest of the night.
Penn was 12 for 16 from the free-throw line; George Mason was 26 for 36.
"Hopefully we can keep guys off the line and rely on our help and trust our teammates," Allen said.
Allen hit all three of his field goals and all eight of his foul shots to score 14 first-half points. He finished with 24 points to lead George Mason.
Tony Hicks led the Quakers with 23 points and six assists.
The Quakers were aggressive early, hitting seven of their first nine shots en route to an 18-8 lead. Hicks hit a corner three-pointer early in the first half and George Mason coach Paul Hewitt called timeout. Hicks scored 10 first-half points but was forced to the bench with five minutes to play with two fouls.
Hicks hit Fran Dougherty with a backdoor pass for a dunk to give the Quakers a 30-24 lead. Dougherty did his damage from both the inside and outside, scoring 10 first-half points. He finished with 17.
After being outrebounded by 43-26 in a loss to Rider on Dec. 29, Penn was more active on the glass early. The Patriots dominated the Quakers on the glass in the second half and outrebounded them by 36-30 overall.
"I feel like every game this year we have played pretty good basketball, but we haven't played our best basketball," Hicks said. "Not even close."
Penn returns to the Palestra on Saturday at 4 p.m. to face La Salle.