Freshman Taquan Dean pulled down eight rebounds to go along with 17 points as the Cardinals knocked off East Carolina 82-67 in front of 19,502 fans in Freedom Hall.
Louisville (20-5, 10-4 C-USA) trailed the Pirates 36-31 at the half, but opened the second stanza with a 17-0 run and coasted to the victory.
"I'm very proud of the fact that we have 20 victories," Pitino said. "We basically are starting over at certain things (with the loss of Stone and Myles) and we have to become a better zone team and change our man-to-man defense. We are basically reinventing ourselves."
Stone sat out the game while the NCAA investigates whether he received improper benefits from his AAU coach Mark Komara. Myles is lost for the season with a torn Patella Tendon suffered in Wednesday's loss to Marquette.
"I thought Otis (George) did an outstanding job today," Pitino said. "Kendall (Dartez) seemed to get a tired, but he played 36 minutes. Kendall is not yet in condition to play 36 minutes, so it is something we need to work on."
Louisville exploded out of the gate to begin the second half, forcing East Carolina into turnovers on eight of their first nine, second half possessions.
Francisco Garcia drove the lane and scored and after a missed three-pointer by Travis Holcomb-Faye, Gaines hit a lay up. Dean stole the inbounds pass and nailed a three-point shot and Gaines hit another jumper. After a Dartez steal, Garcia knocked down a three to push the lead to 43-36.
Garcia then made a steal that lead to a Dartez dunk and after the Louisville press forced another turnover, Dartez hit one of two from the foul line. After another Pirate turnover, Gaines hit a jumper before ECU finally broke the scoring drought with a free throw from Moussa Badiane.
"We started taking good shots and our press was outstanding," Pitino said of the second half run. Gaines led the Cardinals in scoring with 30 and Garcia added 15.
For East Carolina (12-14, 3-12) Derrick Wiley poured in 29 points and pulled down 11 rebounds while Gabriel Mikulas and Holcomb-Faye each added 12 and Badiane pitched in 11.
The Pirates out-rebounded Louisville 38-35 and shot 49 percent from the floor to Louisville's 42.9 percent. The Cardinals forced ECU into 23 turnovers while only committing 12.
Next up for Louisville will be a trip to DePaul on Wednesday night. Tip-off is scheduled for 8:30 in Chicago and will be broadcast locally on WDRB Fox 41.