The Dragons held the Tribe to fewer than 10 points in each quarter en route to a historic win.
Drexel (20-6, 12-2 Colonial Athletic) reached 20 or more victories in back-to-back seasons for the first time as a program. Last season saw a 22-11 mark.
Bailey Greenberg had a team-high 12 points on 6-of-11 shooting, while Kelsi Lidge added 10 points and eight rebounds.
The Dragons have now won 11 straight at home, and 17 of their last 20 games overall.
With four games to go in the regular season, the team next faces conference frontrunner James Madison on Friday. Drexel trails JMU by one game in the loss column in the CAA
The Owls could not keep up with the nation's No. 1 team in a road drubbing.
Pacing the team was Emani Mayo with 17 points. The Huskies had six in double figures, including Katie Lou Samuelson, who scored a game-high 27 points.
Temple dropped its fourth-straight game to fall to 2-11 in the American Athletic Conference and 10-16 overall.
Missing one of their top scorers in Adrianna Hahn due to injury, the visiting Wildcats came up just short against the Big East-leading Blue Demons.
Kelly Jekot notched 17 points to lead four players in double digits for Villanova (20-7, 10-6 Big East). Alex Louin followed with 13 points, seven rebounds and six assists, and Jannah Tucker and Mary Gedaka scored 12 each.