The Cavaliers beat the Chicago Bulls 145-134 in overtime, with Mitchell scoring a career-high and franchise record 71 points on 22-of-34 shooting, hitting seven-of-15 from long range and 20 of his 25 free throws.
In doing so, he beat his own personal best by 14 points after he scored 57 in a playoff loss with the Utah Jazz in 2020, and it was 25 points better than his previous regular season high of 46.
Mitchell added 11 assists and eight rebounds to his stat line, meaning he scored or assisted on 99 of his side's 145 points – the second-most ever, trailing only the legendary 100-point game from Wilt Chamberlain back in 1962 when he was responsible for 104 points.
Adding to his heroics, he single-handedly forced overtime when he intentionally missed a free throw with three seconds remaining in regulation, before getting his own rebound and putting it back in to tie the contest.
Mitchell went on to outscore the Bulls 13-4 by himself in the extra period, putting the finishing touches on his unforgettable night.
Speaking after the game, Mitchell said he has never scored that many points at any level, except for in video games.
"Never – except [NBA] 2K, in 2K for sure," he said. "When I first got into the league I played as the Jazz and was shooting it every time.
"I don't think I did it this efficiently in 2K, but no I never have [scored 71 at any level]. The closest I think I got was in the bubble with 57 – but that was in a loss, so this feels a lot better."
When asked how it feels to join Chamberlain, Kobe Bryant, Elgin Baylor, David Robinson, David Thompson and Devin Booker as the only players to reach the 70-point mark, Mitchell was initially lost for words.
"It's humbling," he said. "I'm speechless, to be honest with you.
"For me, not only did I do that, but I did it in an effort when we came back and won – and it was how we won. That's really what, for me, was like 'man, this is nuts'.
"I'm extremely blessed, I'm humbled that I'm in that company, in that group. I've always believed I can be one of the best players in this league, but I've got to keep working.
"This is a big milestone, but at the end of the day those guys have all won at the highest level, and that's my ultimate goal, but to be there in the record books with them is truly incredible."
Team-mate Kevin Love was in Cleveland for their tremendous run of four consecutive trips to the NBA Finals with James and Irving, but he declared this as the best performance he has ever witnessed in person.
"In my 15 years, that's the best performance I've ever seen, ever been a part of," he said.
"I've seen some special ones, I was talking about Kyrie here against Portland when he had 55, LeBron in Game 1 of the 2018 Finals, 57 for Kyrie in San Antonio – but this one takes the cake."
Head coach J.B. Bickerstaff echoed that admiration for Mitchell's display.
"We were treated tonight to one of the greatest performances in the history of the game," he said. "Every single play that he made was a play that was necessary.
"Donovan has never put himself above the team, so how can you not root for a guy like that? I told everyone else to get out of the way."
The win improves the Cavaliers' record to 24-14 to occupy the fourth seed in the Eastern Conference, while they boast the fourth-best home record in the league at 17-4.