In a stunning upset, defending champion Novak Djokovic was bounced out of the Australian Open by unheralded Denis Istomin on Thursday.

Istomin, from Uzbekistan and ranked No 117 in the world, ousted the six-time Melbourne winner 7-6 (10/8), 5-7, 2-6, 7-6 (7/5), 6-4 in just under five hours at Rod Laver Arena.

It was Djokovic's earliest Grand Slam exit since Wimbledon 2008, when he was beaten by Marat Safin in the second round.

It was also only Djokovic's second loss to a player outside the top 100 in seven years, after his defeat to 145th-ranked Juan Martin del Potro at last summer's Rio Olympics.

"He obviously played above his level, but you have to give him credit for that," Djokovic said.

"Many things came together for him today. He's a well-deserved winner. No doubt, he was the better player in the clutch moments. There's not much I could do."

Istomin, who got into the main draw as the winner of the Asia wild-card playoff last month, said it was the high point of his playing career.

"It is the biggest win for me ... it means so much," 30-year-old Istomin said, struggling with his emotions.

"Now I can feel that I can play with these guys and be with them on the same level.

"I feel sorry for Novak. I was playing so good today. I mean, I also surprised myself."

Djokovic was bidding to win a record seventh Australian Open and overtake Aussie Roy Emerson, who won six in the 1960s.

It was a miserable start to the Grand Slam season for the Serb, who surrendered his No 1 world ranking to Britain's Andy Murray last year and fell to second in the world for the first time since June 2014.

Istomin played at an extraordinary level from the opening game, which took just 16 minutes and heralded the impending struggle for Djokovic.

No escape

Last year Djokovic survived an epic four-and-a-half hour five-set match against France's Gilles Simon in the fourth round here, but this time there was no escape.

Istomin broke the defending champion's service in the seventh game before Djokovic broke back in the following game as the marathon first set went to a tiebreaker.

Djokovic had two set points but it was Istomin who grabbed the set 10-8, ending an 85-minute struggle.

The 12-time Grand Slam champion had more early problems when he clutched his left hamstring after stretching for a volley in the third game of the second set, and called for the trainer at the next changeover.

Istomin held two set points at 5-4 for a two-love lead, but Djokovic fought them off and broke the Uzbek in the next game before leveling the match after almost two and a half hours.

Istomin looked to be tiring when he dropped three straight service games as Djokovic surged back to take the third set and climb in front for the first time.

But Istomin wouldn't go away.

The Uzbek broke Djokovic's serve early in the fourth set and had a set point at 5-4, but the Serb saved it.

Istomin had control of the tiebreaker and got to 5-1 before he took the match into a fifth set with a second-serve ace on his fourth set point.

He was too strong in the decider, breaking Djokovic's serve in the fifth game and admirably handling the pressure to serve it out.

He only needed the first of his two match points to claim victory when Djokovic's return was long.

Istomin will look to keep the magic alive in his third-round match against 30th seed Pablo Carreno Busta of Spain.

Uzbekistan's Denis Istomin celebrates eliminating defending champion Novak Djokovic from the Australian Open in Melbourne on Thursday. Issei Kato / Reuters