The win concluded a turbulent end to the regular season, which saw Louisville (21-6, 11-5 American) win 18 in a row and climb as high as No. 3 in the Top 25 poll, but the Cardinals lost five of their final eight games and finished second in the American Division behind Marquette.
"I told everyone that February was going to be a tough month, but you don't expect to lose (Ellis Myles) and have all the distractions we've had," said Louisville Coach Rick Pitino. "Things have to fall in our laps to win."
The Cardinals played without injured forward Ellis Myles and forward Marvin Stone was held out because of the re-opening of an NCAA investigation.
"Everything has changed and we haven't had a lot of time to work on it," Pitino said. "What's unsettling about the Marvin situation is that you don't know what's going to happen. I believe the NCAA is there for the student-athlete. I think he'll be back, in my estimation. As coaches, we've got to comply to the NCAA rules and be responsible for the program."
Louisville turned the game into a rout midway through the first half.
In his final regular season game, Gaines had eight of his 11 first-half points during a 24-9 burst over the final 10:53 of the first half. That turned a tenuous 25-24 lead into a 49-33 cushion at halftime.
"That was an awesome performance by Louisville," said Charlotte Coach Bobby Lutz. "Marquette is probably the best team in the conference, but college basketball is all about matchups, and we don't match up with Louisville very well."
In the second half, Gaines' unselfishness was on display. He had five assists during the final 20 minutes and scored his final regular-season basket with 17:19 remaining that gave Louisville a 58-38 lead.
In their third 41-point win of the season, the Cardinals did everything right. They shot a season-high 59 percent, hit 13 three-pointers and concluded their best regular season since the 1996-97 campaign.
Charlotte (13-15, 8-8) was led by Demon Brown, who scored 12 points.
Brown, who came in leading the nation in three-pointers, shot just 4-of-11 and missed his final five attempts from beyond the arc after making his first two.