Jewell Loyd scored 17 points, Kayla McBride had 13 and Taya Reimer 12 for the Fighting Irish (7-0).
Notre Dame led by 14 points at halftime and maintained it through most of the second half as Penn State got no closer than nine.
Ariel Edwards scored 18 points for the Lady Lions (5-2). Dara Taylor added 14 points and Talia East 12.
Penn State leading scorer Maggie Lucas, who came in averaging 22.2 points per game, was held to just seven points on 1-for-8 shooting.