Natalie Novosel scored 23 points, while double with 16 points and 11 assists as No. 3 83.
Devereaux Peters also had a double-double with 13 points and 13 rebounds for the Lady Irish (10-1), who have won seven straight games.
Samantha Drake scored 21 points and A'dia Mathies netted 17 points for Kentucky (10-1), which played just its second true road game of the season.
Notre Dame took control early and built a 26-17 advantage after Natalie Achonwa made a jumper with eight minutes left in the opening half.
Kentucky fought back and took its first lead when Samarie Walker made a layup to make it a 28-27 game with under five minutes to go.
But the Lady Irish responded by outscoring the Lady Wildcats 19-12 the rest of the half to take a 46-40 lead into the locker room.
Mathies tied the score at 62 midway through the second half with a three- pointer, but the Lady Irish went on an 8-2 spurt to make it 70-64 after Diggins made a layup.
Once again, Kentucky clawed back and took a 75-74 lead with just over five minutes to play when Drake converted a layup.
The Lady Irish, though, countered again with an 11-0 run capped by a Peters layup for an 85-75 lead with 2 1/2 minutes to go. They held on for the win from there.