The Celtics arrived in Charlotte as the hottest team in the league after surging to the top of the Eastern Conference with an 11-2 record.
Joe Mazzulla's side looked to be cruising towards a seventh straight victory after opening up an 18-point lead midway through the second quarter before taking an 11-point lead into half-time.
But a resurgent Charlotte side hit back in the final two quarters, outscoring Boston 54-43 in the second half to send a pulsating clash into overtime.
Miles Bridges then drained a 25-foot three-pointer to put Charlotte 119-116 up with seven seconds remaining.
Tatum earned three free-throws with five seconds left but after sinking the first two, he missed the third, which would have tied the game, before Gordon Hayward made two free throws for Charlotte to seal victory.
"We just played physical," Bridges said after the Hornets win. "We know they're the best team in the league so we knew we'd have to play physical to give us a chance.
"It feels like this could be the start of something for us," added Bridges after what was only Charlotte's fourth win of the season.
Bridges finished with 14 points while point guard LaMelo Ball led the Charlotte scoring with 36, including five three-pointers from 11 attempts. Hayward added 20 points while Mark Williams had 18.
Tatum's 45-point haul included seven three-pointers and came from 15-of-28 shooting from the field, with 13 rebounds and six assists.
Kristaps Porzingis added 17 for the Celtics, who remain top of the Eastern Conference at 11-3.
- Jokic, Malone ejected -
Jokic was tossed in the first half after giving up two technical fouls for disputing calls on separate incidents.
Malone was ejected after arguing a call late in the first quarter.
With Jokic playing no part in the second half, it was left to Reggie Jackson to help shepherd the NBA champions to victory.
Jackson led the Nuggets scoring with 21 points while Kentavious Caldwell-Pope added 20 points.
Antetokounmpo shot 20 of 23 from the field and finished with 13 rebounds and eight assists in a virtuoso individual display which came after a 40-point performance in Saturday's win over Dallas.
Antetokounmpo has averaged 29.9 points per game in November.
Stephen Curry, who brought home the win after playing the entire fourth quarter, led the Warriors scoring with 32 points while Klay Thompson returned to form with a 20-point haul which included five three-pointers.
"At this stage you just need to win a game," Warriors coach Steve Kerr said. "That was the focus tonight. That's why I played Steph the whole fourth. He was brilliant all night."
The defeat leaves San Antonio bottom of the Western Conference.
Paul George's 28-point display helped the Clippers bag their second straight win.