Brittany Hrynko added 14 for the seventh-seeded Blue Demons (29-6). They earned their third appearance in the round of 16 by hitting 14 3-pointers and forcing second-seeded Duke into 21 turnovers with their high-pressure defense.
DePaul will play the James Madison-Texas A&M winner on Saturday in the Lincoln Regional semifinals.
Elizabeth Williams scored 12 points, and seniors Haley Peters and Tricia Liston each added 11 in their final game at Cameron Indoor Stadium.
Duke (28-7) led for only 12 seconds and became the first top-four seed to lose in the tournament.
The Blue Devils - who made four straight appearances in the regional finals - became the first No. 2 seed to lose this early since Xavier lost to Louisville in 2011.
Jasmine Penny added 11 points for DePaul, which has won 18 of 19.
Coach Doug Bruno's team was coming off a 104-100 win over Oklahoma in the first round, the highest-scoring regulation game in tournament history.
It joined Connecticut, Notre Dame and North Carolina as teams to come into Cameron this year and beat the Blue Devils.
They won this one with defense, using relentless pressure against a Blue Devils team with no healthy point guards.
Ka'lia Johnson scored 11 points and Oderah Chidom added 10 for Duke, which lost an NCAA tournament game at Cameron for the first time since 1996 and was denied its 17th regional semifinal berth in 18 years.
Duke had one last chance to make things interesting after Liston hit a layup after a steal to make it 67-60 with 1:45 left and Hrynko missed the front end of a one-and-one.
But Penny blocked Liston's layup, and after the teams traded turnovers, DePaul bled the clock before Duke fouled Jessica January with 1:09 left.
Liston's 3 went in and out, and Rogowski hit two free throws with 42.1 seconds left to push the lead back to 10.
Duke had closed to 49-46 on Chidom's layup with 7 minutes left.
Penny countered with a jumper in the lane and Hrynko followed with a 3 in front of the DePaul bench - and afterward held her shooting hand high for a moment.
Rogowski, who finished with six 3s, hit one to push the lead to 57-48 - the seventh time the Blue Demons countered a Duke bucket with a 3 - and she then gave DePaul a double-figure lead on its next possession with two free throws with 5:02 left.
By then, Duke was on its way to dropping to 21-2 in NCAA tournament games at Cameron.