Defending champion Novak Djokovic crashed out of the Australian Open after falling victim to a stunning five-set defeat at the hands of wild card Denis Isthmian.
Djokovic was chasing a record seventh title in Melbourne, but his pursuit is over for another year after Istomin, ranked 117th in the world, edged a mammoth contest 7-6 (10/8) 5-7 2-6 7-6 (7/5) 6-4.
It means after winning four consecutive grand slams between 2015 and 2016, Djokovic has now gone three tournaments without adding to his tally of 12 major triumphs.
Istomin, meanwhile, goes through to face 30th seed Pablo Carreno Busta in round three.
The 30-year-old has never before gone past the fourth round of a major tournament and this is only his second win in 34 career matches against a top-10 player.
Istomin, however, played the match of his life on Rod Laver Arena, hitting 63 winners, breaking Djokovic four times and showing remarkable resilience when his more distinguished opponent regularly threatened to take hold.
“I’m sorry for Novak,” he said on court afterwards.
“I was playing so well today. I surprised myself as well.
“It was a tough third set, I had cramp in my leg, I don’t know how I held it. I was physically normal today.
“It is the biggest win for me, it means so much. It shows I can play with these guys and be on the same level.”
Istomin, with his fluorescent yellow headband and glasses, is an experienced member of the men’s tour but when Djokovic was beating Andy Murray to win the Qatar Open earlier this month, the Uzbek was losing to Chile’s Christian Garin, ranked 211th in the world, at a Challenger event in Thailand.
It adds another chapter to Djokovic’s recent demise given the 29-year-old had hoped the new season would be a point to revive his form but has merely proven a continuation of last year’s disappointments.
The first six games alone here lasted half the length of a football match as Djokovic had to save six break points just to lead 1-0.
He bashed his racket in frustration when Istomin did break for 4-3 but broke back instantly and an exhausting opening set had to be settled in a tie-break.
Even then it was neck and neck, Istomin with one set point at 6-5 and Djokovic with two in between at 7-6 and 8-7. It was the Uzbek who held his nerve as Djokovic finally fired long at 9-8.
Sparked into life, Djokovic was all agitation and energy, arguing with the umpire one minute and pumping his fist the next. Istomin, however, refused to lie down and he could have clinched the second set with two set points at 5-4.
But Djokovic not only saved both to hold, with a forehand winner and an ace, he seized the next four points in a row to break and win the set.
The turnaround handed the momentum to the Serbian and when he strolled through the third set with three breaks of serve, it seemed Istomin’s race was run.
Instead, the underdog stormed 4-1 clear in the fourth and while again Djokovic clawed his way into a tie-break, again his opponent proved his mettle.
He sealed the set with an ace, thumping his chest as a spellbound crowd prepared for the decider.
Few players have been more ruthless in fifth sets than Djokovic but Istomin was playing like a man possessed and when he drove a backhand winner down the line to break at 3-2, victory was in his grasp.
Djokovic held to make Istomin serve it out at 5-4 but again he held his nerve, opening up two match points. When a Djokovic backhand drifted long, his success was confirmed after four hours and 48 minutes.