It was the first time that world number 2 Djokovic has dropped a set in the first round of the Australian Open since 2006.
While Roger Federer, the holder for the record of most men’s grand slams won, beat Steve Johnson 6-3 6-2 6-2.
In the women’s draw 15-year-old Coco Gauff faced off against idol Venus Williams, a repeat of the pair’s first-round match from Wimbledon last year.
And once again Gauff beat Williams in straight sets in a 7-6 (7-5) 6-3 victory.
Venus’s sister Serena Williams had a much more serene opening round, beating Anastasia Potapova 6-0 6-3 in 58 minutes.
World number one Ashleigh Barty recovered from losing the first set against world number 120 Lesia Tsurenko to win 5-7 6-1 6-1.