Caroline Doty added 11 points for the Huskies (20-2). They shot 45 percent, held Duke to a season-low 24.6 percent shooting and forced 19 consecutive missed shots during a critical stretch of roughly 12 minutes en route to their 10th straight win.
Chelsea Gray scored 13 points for the Blue Devils (17-3), who had won 11 straight overall. It was their first loss at Cameron since UConn visited two years ago.
Elizabeth Williams added 10 points on 3-of-15 shooting for Duke, and her layup with just under 18 minutes left was the Blue Devils' last basket until Haley Peters hit a 3-pointer with fewer than 6 minutes remaining.
Duke trailed by 14 late in the first half before putting together a 12-3 run that bridged the break. The Blue Devils forced five turnovers in the first six minutes of the half, and Williams helped Duke close to 34-29 with a free throw with 17:19 left.
That's when UConn took over and began stretching its lead with 3-pointers. The Huskies hit four - two by Kaleena Mosqueda-Lewis - in a 9-minute stretch before Tiffany Hayes added a bucket in the lane, pushing it to 50-33 with just over 7 minutes left, and Duke didn't get closer than 12 the rest of the way.
Stefanie Dolson added 10 points for UConn, which overcame 21 turnovers by forcing 15 from Duke. The Huskies entered with the nation's toughest defense by shooting percentage, holding opponents to 30 percent. They forced the Blue Devils into their worst shooting night by far - their previous low was 32 percent in a loss to Notre Dame.
The Huskies have dominated this series lately, winning four straight and routing Duke twice last season - including a 36-point loss that ended the Blue Devils' unbeaten start to 2010-11 and a 35-point romp in the NCAA tournament with a Final Four berth on the line.
Unlike those two meetings, this one wasn't over at halftime. Dolson had her per-game average of 10 points by halftime, and she gave UConn its largest lead of the half when her layup with just under 3 minutes left made it 31-17.
Gray had 11 points at halftime on 4-of-10 shooting - with three 3-pointers - while the rest of the Blue Devils were a combined 6 of 24 from the field. Duke's 31-23 halftime deficit marked the first time it trailed at the break, and its 29 percent shooting was a season low for a first half.