Jefferson scored the Timberwolves' first seven points in overtime, helping them overcome the efforts of rookie scoring leader Mayo -- who was picked and traded by Minnesota on draft night.
"When the big horse gets it going like that, it's tremendous," Wolves coach Kevin McHale said.
Mayo had 23 points and Kyle Lowry finished with a career-high 12 assists, but Memphis lost its second consecutive overtime game and sixth in its last seven overall.
Mayo tied it at 89 with 27 seconds left and Minnesota's Randy Foye missed a last-second jumper that would've won it in regulation.
The win helped take the focus off the draft-day deal that saw McHale send Mayo's rights to the Grizzlies for Love, Mike Miller and others.
So far the deal has heavily favored the Grizzlies, as Mayo entered the game averaging more than 20 points and Love 7.5. But Love held his own on Monday and contributed down the stretch, with his 17 points the first time he was in double figures since Dec. 10 against Denver.
Reporters posed several questions to Mayo and Love about their first NBA meeting and the fallout from their draft-day swap, but both played it down.
"Get it out the way," Love said. "It's overrated but it's going to be there. I heard some of the screams tonight -- 'We want Mayo, we want the juice' -- but it is what it is."
Mayo found it hard to talk about Love after watching Jefferson dominate all night.
"Kevin is a good player. He made some key plays," Mayo said. "We had a lot of pressure trying to focus on Al, it opens the door up for Kevin and he's a good player."
The Wolves trailed by eight in the fourth quarter, but led by Jefferson and Love, went on a 14-4 run to reclaim the lead. Four other Grizzlies finished in double figures.
Mayo scored seven consecutive points late in the fourth quarter and nearly carried his team to a victory. But he also had a costly turnover with 53 seconds left and his team trailing by one.
The Wolves rebounded from a dismal second quarter to win at home for the first time since Nov. 19.
Minnesota started the game 10-for-11 from the field, but missed 19 of its next 22 shots and entered halftime trailing by seven. The Wolves managed only one field goal in the second quarter, a franchise low. Their eight second-quarter points and 32 first-half points were both season lows.
"We sent basketball back to about 1952 in that second quarter," McHale said.
Things turned around in the second half once Minnesota started pounding the ball back down to Jefferson.
"We got stopped in the second quarter and when halftime came we got cussed out real bad," Jefferson said. "Mac got us fired back up. It was plain to see when we were out there moving the ball, we were scoring very easily."
Minnesota missed all 12 of its 3-pointers in the first half and finished a season-worst 1-for-15 from beyond the arc. In its previous two games, Minnesota hit 21 of 37 3-pointers.
Despite Minnesota's period of ineptitude, Memphis coach Marc Iavaroni thought his team looked lost at times throughout the game.
"We were just bumping into each other and they were shooting a lot of layups in the second half," Iavaroni said. "Jefferson on top of that is pretty tough for our rookies to handle."
Miller did not play against his former team and has now missed the last four games with a sprained right ankle.
If the Wolves are going to get things going in the right direction, this is the time to do it. Monday's game began a stretch of seven of 10 contests against teams currently below .500. ... Steve Francis, acquired in a trade on Dec. 24, was again inactive for Memphis. ... Mayo has scored in double digits in 29 of 31 games. Love has hit double digits only eight times. ... Marc Gasol and Darrell Arthur fouled out for Memphis.