Returning to Rod Laver Arena for the first time since beating older sister Venus while pregnant in the 2017 final, Williams crushed German Tatjana Maria 6-0 6-2 in 49 minutes on Tuesday.
Williams will resume on Thursday against Chinese wildcard Peng Shuai or Canadian Eugenie Bouchard as she continues her chase for an eighth Open crown, which would draw the American level with Margaret Court with 24 major singles titles.
Williams conceded only five points in racing through the first set before Maria saved face by finally getting on the board after dropping the opening nine games.
But victory was inevitable for Williams, who remains undefeated this summer following three straight-set wins at the Hopman Cup in Perth.
Earlier, Karolina Pliskova also continued her unbeaten start to 2019 with a 6-3 6-2 victory over fellow Czech Karolina Muchova.
Pliskova pulled out of last week's Sydney International after winning her season-opening event in Brisbane and reaped the rewards with a polished start to her Open campaign.
In addition to five aces, Pliskova clubbed 21 winners to book a meeting on Thursday with either American Madison Brengle or Japanese qualifier Misaki Doi.
"I was hitting great even in the warm up. I think it's a good start," said the 2016 US Open runner-up and former Melbourne Park junior girls' champion after claiming her sixth win of the year in Australia.
"I feel happy here. I don't know why. I always love playing here."
Another former Flushing Meadows finalist also progressed on Tuesday, with American 17th seed Madison Keys taking out young Australian wildcard Destanee Aiava 6-2 6-2 on Rod Laver Arena.
It was Keys' first match of 2019.
"I was having issues with my knee towards the end of last year and I ran out of time (to play any lead-up tournaments)," she said.
"Mostly I'm just happy that I did most things pretty well."
Keys will play either Frenchwoman Pauline Parmentier or Russian Anastasia Potapova for a place in the third round.