Devin Thomas had 19 points, 10 rebounds and five assists for the 12th-seeded Demon Deacons (17-15), who recorded their first win in the league's tourney since 2007.
The overdue victory sets up a second-round meeting with fifth-seeded Pittsburgh on Thursday.
Arnaud William Adala Moto drained all four of his shots and finished with 12 points for Wake Forest, which led almost the entire way despite committing 15 turnovers to Notre Dame's six.
The Demon Deacons, however, shot 61 percent and drained 7-of-10 3-pointers.
Notre Dame (15-17) wrapped up its inaugural campaign in the ACC with three straight losses.
The 13th-seeded Fighting Irish closed to within six at 70-64 with 1:44 remaining, but Wake Forest was efficient at the foul line down the stretch.
Pat Connaughton scored 19 points to lead Notre Dame, which got 14 points and nine rebounds from Zach Auguste.
The Fighting Irish had won at least one conference tournament game in each of their last five years in the Big East.