World number one and defending champion Victoria Azarenka was unable to match the third seed's ruthless dominance but also progressed to the second round, while Andy Murray steadied his grand slam nerves with a controlled three-set victory.
Second seed Roger Federer also came through his first round match comfortably enough, beating Frenchman Benoit Paire 6-2 6-4 6-1 to embark on his campaign for an 18th grand slam title.
After an underwhelming opening day of the tournament on Monday, the sheer breadth of star quality on display on the show courts almost ensured a better day two under the sunny skies at Melbourne Park.
There is no bigger personality in tennis than Williams, who is chasing a third successive grand slam title after wins at Wimbledon and the US Open, and the American almost inevitably hogged the spotlight despite playing out on Hisense Arena.
Rampaging towards victory over Romania's Edina Gallovits-Hall, the 31-year-old turned her ankle after hitting a forehand from the tramlines and lay prone on the court for a couple of dramatic minutes until medical staff arrived.
The injury immediately recalled the fall that injured her other ankle at the Brisbane warm-up last year and ultimately ended her 2012 Melbourne Park campaign.
"It was definitely a lot of pain," she recalled. "Also a little bit of the memory, as well. So it was definitely a little bit of both. But also at the same time trying to gather myself together and trying to make sure that I can continue."
She was soon back up, ankle strapped and in pain, to complete the victory and said nothing would stop her from taking to court for her second round tie against Magdalena Rybarikova or Garbine Muguruza.
"I'll be out there," she said. "I mean, unless something fatal happens to me, there's no way I'm not going to be competing. I'm alive. My heart's beating. I'll be fine."
While Williams is pursuing her 16th grand slam single's title, Murray is hoping to accumulate his second after his breakthrough triumph at the U.S. Open last year.
The Scot, who like Williams opened his season by winning the Brisbane warm-up, made short work of Dutchman Robin Haase with a 6-3 6-1 6-3 victory in the first match on Rod Laver Arena.
"I thought I did a pretty good job from the start of dictating the points and not giving him too many freebies," the third seed said.
"There's nerves in the build-up. You just got to try and focus and play solid, you know, not make too many silly mistakes. I did a good job of that today."
Women's top seed Azarenka was less convincing in her 6-1 6-4 victory over Romania's Monica Niculescu, forced to come back from 3-0 down in the second set to prevent the match going to a decider.
With second seed Maria Sharapova having also won her first round match without conceding a game, Azarenka might have been looking to make a similar statement but the Belarussian said she was just happy to be back on court.
"I couldn't wait to get out there and play," said the 23-year-old, who pulled out of the Brisbane warm-up after suffering a toe infection following a pedicure.
"It's been a long week preparation... I think I had a good first match. That's what I needed to get into that competitive spirit, which I did. I'm happy."
After only two seeds fell in the entirety of day one of the tournament, women's seventh seed Sara Errani and 12th ranked Nadia Petrova departed in quick succession on Tuesday.
While Errani's 6-4 6-4 loss to Carla Suarez Navarro was not a huge shock, 42-year-old Kimiko Date-Krumm's 6-2 6-0 victory over Petrova earned her a place in the record books as the oldest winner of a women's singles match at the tournament.
Former world number one Caroline Wozniacki looked like she might also be on her way home but the 10th seeded Dane battled back from a set down to beat German Sabine Lisicki 2-6 6-3 6-3.
Her extended match kept boyfriend Rory McIlroy, the golfing world number one, from his bed in Abu Dhabi where he signed a multi-million sponsorship deal on Monday.
"Great comeback by @CaroWozniacki! Off and running at the Australian Open... Now I can get a few more hours sleep!," the Northern Irishman tweeted.
