Kayla McBride popped in 18 points and handed out seven assists for the Fighting Irish (35-1), who reached the NCAA Women's Basketball Tournament Final Four with a 30th straight win.
Natalie Achonwa (17 points, 13 rebounds) and Jewell Loyd (17 points) also provided key points as Notre Dame used a second-half surge to pull away, claiming the Norfolk, Va., region.
They will next face top-seeded Connecticut in the Final Four April 7 in New Orleans.
The Blue Devils (33-3) were paced by Tricia Liston with 19 points in the loss -- their fourth straight in a regional final.
Haley Peters added 15 points and 10 boards for Duke.