US Open champion Naomi Osaka also stormed through, but world number one Simona Halep was lucky to stay alive, needing to dig deep and claw back from a set down before beating Kaia Kanepi 6-7 (2/7), 6-4, 6-2.
American giant Williams is bidding to match Margaret Court’s record of 24 Grand Slam crowns on her first return to Melbourne Park since winning in 2017 while eight weeks pregnant.
Now 37, she kept a low profile in the lead-up to the opening major of the year and came out of the blocks flying against fellow mum Tatjana Maria, pummelling her German opponent 6-0, 6-2.
Sporting a striking jade green jumpsuit and fine mesh stockings on Rod Laver Arena, the 16th seed wasted no time in getting out of the blistering Melbourne heat and said it was good to be back.
“The last time I was here I was pregnant and playing at the same time which is insane,” she said. “It’s weird walking back on -– by myself this time -– it feels good. I have so many memories from last time I was here.”
Bidding for an eighth Melbourne Park crown, few are betting against Williams despite her lowly seeding and she next faces Canadian Eugenie Bouchard who eased past China’s Peng Shuai.
Williams played at the mixed teams Hopman Cup in Perth this month, but her appearance on Tuesday was her first outing on tour since a meltdown in losing the US Open final to Osaka in September.
Japan’s Osaka, seeded four, wasted little time in dispatching Poland’s Magda Linette 6-4, 6-2 and will next play Tamara Zidansek of Slovakia.
Like Williams, Djokovic is also gunning for a slice of history as he looks to win a seventh title. Fellow six-time champion Roger Federer is aiming for the same.
The Serb blasted past American qualifier Mitchell Krueger 6-3, 6-2, 6-2 to set up a clash with Jo-Wilfried Tsonga, who he beat in Melbourne to win the first of his 14 Grand Slam crowns back in 2008.
“It feels great to be healthy and back on this court again,” he said of Rod Laver Arena.
“I had a tremendous success in the last six months. It got me to a great position. Hopefully I can follow up on this victory tonight with a good performance.”
– Escape act –
Fourth seed Alexander Zverev, who is looking to win his first Slam title and establish himself as a serious threat to Djokovic, Federer and Rafael Nadal, cruised past Aljaz Bedene 6-4, 6-1, 6-4.
“I’ve had about 86 injuries and the ankle is still a bit swollen,” said the 21-year-old. “But I’ve done everything right in my preparation. Now I either play well or I don’t.”
But eighth seed Kei Nishikori, who won in Brisbane last week, had a lucky escape.
The Japanese star looked down and out against little known qualifier Kamil Majchrzak, losing the first two sets before the Pole began badly cramping.
He bravely fought on before calling it a day after winning just two of the next 17 games.
Elsewhere, 2014 champion Stan Wawrinka benefited from an opponent pulling out, with Ernests Gulbis calling it quits after hurting his back in the second set.
Among the women, sixth seed Elina Svitolina easily progressed, as did Williams’ sister Venus, who incredibly played her first Grand Slam tournament 22 years ago.
But two-time champion Victoria Azarenka was bundled out, along with 10th seed Darya Kasatkina.
Seventh seed Karolina Pliskova, who has made the quarter-finals in her last two appearances at Melbourne Park, went through, as did American Madison Keys, who reached the semis at the French and US Open last year.