The 37-year-old, seeded third, is bidding to extend his all-time leading men's Grand Slam record to 21 title and would capture a 100th ATP tournament win in the process.
Serb Djokovic could then play a rematch of his 2008 final triumph over Frenchman Jo-Wilfried Tsonga in the second round, with a possible quarter-final against Kei Nishikori to follow.
Men's second seed Rafael Nadal opens against Australian James Duckworth, fourth seed Alexander Zverev starts against Slovenian Aljaz Bedene, and last year's runner-up Marin Cilic plays another local in Bernard Tomic.More news: 'Gully Boy' trailer: Ranveer and Alia steal the show
But the toughest-looking opener on paper pits Australian 2015 quarter-finalist Nick Kyrgios against Canadian 16th seed and 2016 Wimbledon finalist Milos Raonic.
The Spanish 22nd seed defeated Novak Djokovic on his way to the title in Doha last week while concerns about Murray's fitness grew as he struggled through a practice match against world number one Djokovic at Melbourne Park on Thursday.
Federer's first-round test comes in the shape of Uzbek Istomin, the Swiss having won each of their six meetings, and they are in the same quarter of the draw as Andy Murray, who is unseeded and meets Spaniard Roberto Bautista Agut first up.More news: Mysterious radio signals from deep space detected
On the women's side, all eyes will be on Serena Williams as she aims for Grand Slam number 24.
World number one Djokovic, who produced a strong comeback previous year, was the top seed of men's singles.
Unseeded Estonian Kanepi knocked Halep out of the first round at Flushing Meadows past year, making the Romanian the first top seed to lose at that tournament's earliest stage.More news: Audi Showcase Virtual Reality Features at CES 2019
"The first time I came back here and hit on the courts, I thought, 'OK, I'm home,"' the third-seeded Wozniacki said of her return to Melbourne Park.
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