Men's top seed Djokovic, who was defending his title when he lost to Istomin, will first meet a qualifier in his bid for a record seventh Melbourne title and third Grand Slam crown in succession following wins at Wimbledon and the U.S. Open.
Fellow American great Chris Evert said the shadow of the US Open final controversy would not hang over Williams' career.
Wozniacki also has a question mark over her fitness after the 28-year-old Dane revealed her battle with rheumatoid arthritis last October, but has since claimed that she has learnt to live with it.
She last won a Major at the 2017 Australian Open when she was four weeks pregnant.
When it comes to Williams, who is seeking a record-equalling 24th Grand Slam singles title at the January 14-27 Australian Open, Evert believes it is her remarkable journey from the hardscrabble courts in Compton where she learned the game to the top of the tennis world that will be remembered most.
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A rare coin found by a high schooler in his lunch money has been valued at nearly $1.7million, following the owner's death. When they became dislodged, they were printed and circulated with the millions of steel copies.
Serena Williams' legacy will not be tarnished by what happened at the US Open final past year, 18-time Grand Slam champion Chris Evert said ahead of the Australian Open, scheduled to begin on Monday.
"The fact that she could break the record for overall grand slams, that will overshadow everything at the end of the day". Among those looking to halt Serena's charge: world number one Simona Halep, defending champion Caroline Wozniacki and US Open victor Naomi Osaka.
The shock diagnosis came after Wozniacki had returned to number one and taken her WTA tour title tally to 30 with victories not only in Melbourne, but also Eastbourne and Beijing.
She warmed up for Melbourne by making the semi-finals of the Brisbane International last week, where she blamed a poor attitude for losing to Lesia Tsurenko.
"I think she's fresh that's one thing, but everyone else is fresh too", said Evert. But coming from Constanta [her home city], from nowhere, and becoming the best, is pretty huge for a Romanian, and for me as a person. "I didn't experience her life".
He retired in the quarter-finals against Marin Cilic a year ago in Melbourne and suffered yet another knee injury that forced him out of the US Open semi-finals before ankle surgery in November. "It means so much to me".