The Huskies (17-2, 6-1 Big East) had won their previous four by an average of 44.5 points, and this one never was in doubt, either. They jumped out to a big lead in the opening minutes and snapped DePaul's 28-game home winning streak.
Lewis set the tone, scoring 18 points as the Huskies built a 53-23 halftime lead. The freshman hit 5 of 7 3-pointers in the game and grabbed seven rebounds.
Tiffany Hayes delivered her eighth straight double-digit scoring game, finishing with 14 points.
The Huskies outshot the Blue Demons (15-5, 3-3) 54.7 percent to 27.8 percent overall. They were 9 for 19 on 3-pointers compared to 8 of 26 for the Blue Demons and outrebounded them 46-22. They also forced DePaul into 23 turnovers, resulting in 33 points.
DePaul got 18 points from Brittany Hrynko but never had a chance in this one. The result was its first home loss since a rout by Connecticut on Feb. 10, 2010.
Saturday's rout came a day after the announcement that Blue Demons coach Doug Bruno will serve as an Olympic assistant to Connecticut's Geno Auriemma, along with Washington Mystics assistant Jennifer Gillom and Atlanta Dream head coach Marynell Meadors. All four posed for a photo before the opening tip. Once the game started, Connecticut wasted no time taking control.
Coming off lopsided wins over No. 24 North Carolina and Cincinnati, the Huskies scored the game's first 11 points while building a 16-2 lead. The Blue Demons were within 28-16 after a jumper by Jasmine Penny with 5:30 left in the half, but things quickly got out of hand after that.
Connecticut reeled off 13 straight, with Mosqueda-Lewis making a 3 and two free throws to cap the run, and led by as much as 33 in the closing seconds of the half.
Whether they were shooting from inside or long range, the Huskies simply weren't missing.
They outscored DePaul 18-6 in the paint and 18-1 off turnovers while hitting 16 of 30 shots, including 6 of 11 3-pointers, in the half.
UConn had a brief scare early in the game. Guard Caroline Doty, who has had a career filled with knee injuries, pulled up while driving into the lane with 17:40 left. She left the game, went to the locker room for observation, then returned and then sat at the end of the bench.
"I didn't see what happened to Caroline," Auriemma said, according to The Hartford Courant. "Caroline's knee is sore every single day and likely will be every day for the rest of her life after three operations. She said she just felt something and there was some swelling, which isn't unusual. But the decision was made to keep her out and no one is really concerned about it. There is no alarm for sure, at all."
This was UConn's seventh game since Jan. 4.