Defending champion and six-time winner Novak Djokovic was sensationally knocked out in the second round of the Australian Open by unheralded Uzbek Denis Istomin in the tournament's biggest shock this year.

The 30-year-old world No 117 played the match of his life to hand Djokovic only his second defeat in seven years at Melbourne Park with a 7-6, 5-7, 2-6, 7-6, 6-4 second-round win that went on for almost five hours on Rod Laver Arena.

Istomin let out a huge roar of delight when he ensured Djokovic's earliest exit from the tournament in more than a decade, the 12-time grand slam champion sending a service return long to end the contest after four hours and 50 minutes.

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"First of all, I feel sorry for Novak. I was playing so good today," Istomin said on court.

"I mean, I surprised myself also today. I want to thank my team who do a good job. Amazing. So much emotion on my mind so I cannot hold it you know but I want to say thanks very much for coming to support me."

The wildcard, who hit 63 winners, edged the first set but simply refused to fold when second seed Djokovic hit back to win the second and third sets.

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Clinching the fourth on another tie-breaker to send the match into a decider, Istomin grabbed an early break in the fifth and held his nerve to deliver a famous victory.

"I mean it was tough, since third set I get cramping in my leg so I don't know how I hold it," he added. "But I was physically normal today."

After the biggest win of his career, Istomin moves on to a third-round meeting with Spaniard Pablo Carreno Busta.

It was 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 year's Rio Olympics.

"He played obviously above his level. You got to give him credit for that," Djokovic said. "Many things came together for him today. He's a well-deserved winner.

"He deserved to win. No doubt, he was a better player in the clutch moments. There's not much I could do."