Kyrgios was punished for being unseeded at a grand slam event for the first time in more than three years, striking former Wimbledon finalist Milos Raonic in an explosive first-round match-up at Melbourne Park.
If he gets past the 16th seed, he could face 2014 champion Stan Wawrinka, another dangerous floater in this year's devilish men's draw, with world No.4 Alexander Zverev Kyrgios's projected last-16 opponent.
Tomic, back in the main draw after failing to qualify last year, has an even more challenging opener against last year's runner-up, Croatian sixth seed Marin Cilic.
It could have been worse for Kyrgios, a former Open quarter-finalist who has slipped to 50th in the rankings, and Tomic, three-times a second-week challenger at the season's first major.
Instead, top-seeded Djokovic plays a qualifier, while defending champion Federer - who, like the Serb, is chasing a record seventh Open men's singles crown - drew Uzbeki Denis Istomin.
Playing his first event since the US Open in September, Nadal opens his bid for an 18th major title against Australian wildcard playoff winner James Duckworth, whose wretched first-round draws at the slams continued.
De Minaur seemingly has a much smoother path to the second round than most of his compatriots, the 27th seed starting against Portugal's world No.103 Pedro Sousa.
But de Minaur, seeded at a slam for the first time following his meteoric rankings rise in 2018, could meet second seed Nadal as early as round three.
Fittingly, given her rich vein of form and much-deserved first-time top-16 seeding, Barty looks the best bet to go deepest of the 20 Australians so far in the main draws.
With victories over three grand slam champions already this summer, including world No.1 Simona Halep on Wednesday, Barty says she fears no one and looms as Australia's best hope in more than a decade to break Australia's 41-year women's title drought.
But the 22-year-old insists her immediate focus is on winning this week's Sydney International to complete the perfect Open build-up.
"I'll worry about that (the Open) come Sunday or Monday, whenever we're finished here," Barty said after storming into the semi-finals on Thursday with a straight-sets defeat of world No.12 Elise Mertens.
Australian No.2 Daria Gavrilova starts her Open campaign against Slovenian Tamara Zidansek, Ajla Tomljanovic faces Britain's Sydney-born 2017 semi-finalist Johanna Konta and veteran Samantha Stosur meets Ukraine's Dayana Yastremska first-up.