Shabazz Napier scored 16 points to lead the Huskies (14-3, 4-2 Big East), who had also snapped Notre Dame's previous 45-game winning streak in South Bend back in 2009.
Notre Dame led at halftime 25-24, but was outscored 43-28 in the second half.
Andre Drummond chipped in 10 points and gathered up 13 rebounds, and Alex Oriakhi tallied 12 points and seven boards in UConn's second consecutive victory.
Eric Atkins led Notre Dame (11-7, 3-2) with 20 points. Scott Martin scored 12 and had nine rebounds.
Rebounds played a big role in the game as both teams shot under 47 percent from the field. The Huskies had 47 boards to 30 for the Irish.