Uzbek Denis Istomin pulled off an Australian Open upset for the ages when he sent reigning champion Novak Djokovic tumbling out of the years first Grand Slam in a near five-hour epic on Thursday.

The 30-year-old world number 117 played the match of his life to hand the six-times champion only his second defeat in seven years at Melbourne Park with a 7-6(8) 5-7 2-6 7-6(5) 6-4 second-round win on Rod Laver Arena.

Denis Istomin expressed his delight for the victory.

"It is the biggest win (of my career) for me and means so much, now I feel I can play with these guys and be with them on the same level," said Istomin.

"From the third set I had cramp in my leg, I don't know how I held it. I was playing so good. I surprised myself."

Istomin had two years out of the game after breaking his leg in a car accident in 2001 and spending three months in hospital.

Coached by his mother Klaudiya, he dropped out of the top 100 in 2016 and was given a wildcard to play the Australian Open.

Prior to his win over Djokovic, Istomin had won just one of 33 matches against a player ranked in the world's top 10.