Taylor Thornton and Lacey Vigmostad each added two goals for the second-ranked Wildcats (18-2), who took charge of the game in the second half and rebounded from a 14-7 loss to No. 1 Florida last week in the American Lacrosse Conference final.
Both of Northwestern's losses this season are to the Gators.
Northwestern will host the winner of Sunday's game between Duke and Virginia in the quarterfinals next weekend. The Wildcats have won six of the past seven NCAA titles, missing only in 2010.
Betsy Mastropieri and Kaitlyn Brosco each had two goals for Notre Dame (13-5), which went 5-5 down the stretch after starting the season 8-0.
Northwestern leading scorer Shannon Smith was held to one goal. She has 249 for her collegiate career, one short of the team's record.
The Irish played their second game without leading scorer Lindsay Powell, who suffered a torn ACL in practice on April 30. She watched from the sideline in a wheelchair.
Neither team opened more than a one-goal lead in the tightly played first half until Northwestern's Smith and Fitzgerald scored 68 seconds apart in the final two minutes to snap a tie and put the Wildcats ahead 5-3.
Northwestern took charge early in the second half and opened a 10-5 lead midway through the period when Amanda Macaluso scored unassisted.
Brosco and Mastropieri scored 3:26 apart to cut it to 10-7, but Vigmostad connected twice in the final minutes to complete the scoring.
Northwestern goalkeeper Brianne LoManto finished with five saves. Notre Dame goalie Ellie Hilling had four saves before being replaced by Allie Murray with 1:43 left.