DeRozan added six assists, three rebounds and three steals while scoring 13 of his game-high 28 points in the fourth quarter as the Bulls improved to 23-10, matching Brooklyn for the Eastern Conference lead.
"I looked up at the clock, I said, 'I've got to make something happen,'" DeRozan said. "I just tried to get enough space to get it up. As soon as it left my hand it felt good."
DeRozan rated the 28-foot game-winning shot among his best buzzer beaters.
"I rank it up there," DeRozan said. "It was one of those games where it felt like nothing was going our way. It felt like we was getting beat up.
"But we grinded it out and won it on a big shot. It was a hell of a win to pull out."
The Bulls, missing coach Billy Donovan due to Covid-19, have thrived despite adversity.
"It's credit to our hard work," DeRozan said. "For our team to be able to hold all those things off and, at the end of the year, to be on top of our conference speaks volumes to what type of team we are."
In the NBA's final game of 2021 and the first game for James since turning 37 on Thursday, the four-time NBA champion delivered a season-high point total on 16-of-26 shooting, going 5-of-10 from 3-point range to lead the Lakers over visiting Portland 139-106.
James enjoyed his 67th career game with 40 or more points, with 27 points and 10 rebounds at halftime.
He contributed 14 rebounds, four assists, two steals and two blocked shots without a turnover in 29 minutes for the Lakers, seventh in the Western Conference at 18-19.
Lakers guard Russell Westbrook delivered his NBA-best ninth triple double of the season, and fourth in a row, with 15 points, 13 rebounds and 12 assists.
Boston's Jaylen Brown and Marcus Smart each scored 24 points and Robert Williams had a triple double with 10 points, 11 rebounds and 10 assists to power the Celtics over Phoenix 123-108.
The visiting Suns fell to 27-8, half a game behind Golden State to stand second in the Western Conference, while the Celtics, whose 46 points off the bench were twice what Phoenix scored, improved to 17-19.
Miami's Jimmy Butler returned from a sprained ankle to score 37 points while Turkish rookie center Omer Yurtseven had 10 points and 13 rebounds to spark the Heat to a 120-110 victory at Houston.
No fans at Raptors win
With new Covid-19 regulations in Ontario keeping fans from attending, Toronto got 31 points and nine assists from Fred VanVleet in his return from the virus to beat the Los Angeles Clippers 116-108.
O.G. Anunoby added 26 points and Pascal Siakam added 25 and a career-high 19 rebounds plus seven assists for the Raptors.
A video tribute to Spaniard Serge Ibaka, a former Raptor star, played to silence in the empty arena.
The Raptors and Clippers each have four players sidelined by Covid-19 while the NBA has about 120 players out in health and safety protocols.
Utah's Donovan Mitchell scored 39 points, Croatian Bojan Bogdanovic added 24 points and 12 rebounds and Frenchman Rudy Gobert had 14 points and 16 rebounds in the Jazz's 120-108 home victory over Minnesota.
Atlanta's Trae Young scored 35 points and passed out 11 assists while Clint Capela added 18 points and 23 rebounds to power the Hawks over host Cleveland 121-118. The Cavaliers had 35 points off the bench from Kevin Love.
Memphis guard Ja Morant scored 30 points to power the Grizzlies over visiting San Antonio 118-105 while Shai Gilgeous-Alexander scored 23 points to lead Oklahoma City over visiting New York 95-80.
Latvian Kristaps Porzingis scored 29 points and grabbed nine rebounds to lead Dallas in a 112-96 victory at Sacramento.