A five-time winner of the Melbourne title, the American did not look troubled by her ankle - injured in Brisbane earlier this month - as he brushed aside Tamira Paszek 6-3 6-2.
In a match which did not start until gone 2300 local time, Paszek stayed level over the first six games - and actually had two break points early on - but from that point Williams' superior power took over.
The 30-year-old, who last won here in 2010 and could not defend last season due to injury, at one point served a game of four consecutive aces. She finished with a total of 12 and held serve throughout.
Afterwards, Williams said she was happy to be back playing in front of the Melbourne fans.
"I haven't been here in over a year so I was a little bit nervous - thank you for getting me through it."
She also said she was happy to play late - the match had been delayed by an earlier four-hour men's contest featuring Lleyton Hewitt.
Williams added: "I'm definitely a night owl - I can stay up all night!"