A week after coming back from 10 points down in the fourth quarter to defeat Dallas, Cleveland conjured an even more remarkable late show to stun Boston, the Eastern Conference leaders.
Boston looked to be cruising to a 12th straight win after a clinical display left them leading 93-71 early in the fourth quarter in Cleveland.
But Dean Wade erupted for 20 points in the final frame, draining a string of three-pointers to haul Cleveland back into the contest.
Wade, who finished with 23 points, made the winning layup with 19 seconds remaining to put Cleveland ahead after Kristaps Porzingis's free throw had helped the Celtics take a 104-103 lead.
Boston thought they had been thrown a lifeline when Jayson Tatum appeared to be fouled as he went for a late shot.
But the call was overturned in Cleveland's favor and time ran out to give the Cavaliers a victory made all the more impressive given the absence of key starters Donovan Mitchell and Max Strus.
"It feels good, my teammates had the trust in me to make those shots," Wade said afterwards.
"Them just having that belief in me gave me the confidence and motivated me, and luckily they went in," added Wade, who was congratulated at courtside by Cleveland native and Kansas City Chiefs NFL star Travis Kelce following the win.
Wade finished with 23 points, including six-of-nine from three-point range, with eight rebounds.
Jarrett Allen had 21 points while Darius Garland and Isaac Okoro added 16 points apiece.
Boston were left wondering where it had all gone wrong after an extraordinary late collapse.
"We just went cold," Celtics coach Joe Mazzulla said. "I thought we had some good possessions where we didn't make the shot. But credit to them - Wade played really well and they made plays down the stretch."
Tatum led Boston's scorers with 26 points while Porzingis added 24 and Jaylen Brown 21.
The Celtics remain comfortably on top of the Eastern Conference despite the loss with a 48-13 record. Milwaukee are second in the standings at 41-21 while Cleveland are third after improving to 40-21.
Durant shines in Suns win
The drama in Cleveland was rivalled by a thrilling battle in Denver later Tuesday, where the Phoenix Suns recovered from blowing a 22-point third-quarter lead to defeat the Nuggets 117-107 in overtime.
Kevin Durant poured in 35 points for Phoenix while Grayson Allen added 28 including eight three-pointers to help the Suns over the line.
But the Suns almost blew their chances of victory after a dismal fourth-quarter display which saw them shoot just five-of-24 from the field.
Phoenix rediscovered their shooting touch in overtime however, outscoring Denver 15-5 to close out the win.
"We missed like 10 straight shots in the fourth quarter...but that's the name of the game, you just stick with it," Durant said afterwards. "In overtime we were able to get stops, rebound and get easy shots."
Jamal Murray topped the Denver scorers with 28 points while Nikola Jokic had 25 points, 16 rebounds and five assists.
In other games on Tuesday, Luka Doncic put up a 39-point triple-double with 10 rebounds and 11 assists, but it was not enough to prevent the Dallas Mavericks falling 137-120 to the Indiana Pacers.
The Pacers spread the scoring around in devastating fashion to overwhelm the Mavericks defence, with nine Indiana players reaching double figures.
In New York, the Philadelphia 76ers stumbled to a 112-107 defeat to the Brooklyn Nets.
In Toronto, the New Orleans Pelicans dished out a humiliating 41-point drubbing of the Raptors, winning 139-98.
Trey Murphy led the Pelicans scoring with 34 points on a night when no fewer than seven New Orleans players made double figures.
"I'm extremely proud of this group - it's a great step in the right direction," said New Orleans head coach Willie Green.
The Pelicans improved to 37-25 to remain in fifth place in the West.
