The American gets her quest for an Open-era record 23rd Grand Slam title underway in a difficult first-round clash against Switzerland's Belinda Bencic in forecast sweltering heat on Tuesday.
It will be one the few matches she has played after a four-month lay-off.
But the 35-year-old, seeded two, is in fighting mood despite being bundled out in the second round of her only warm-up tournament, the Auckland Classic.
"I've been spending so much time on the court. It feels really good to be back, just hitting on Rod Laver (Arena), hitting on all the stadiums, it's a good feeling. I love it here."
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If she gets past Bencic, Williams could then encounter either in-form Briton Johanna Konta, who won this week's Sydney International, or sixth seed Dominika Cibulkova in the quarter-finals.
And then there's Germany's Kerber, who is scheduled to meet her in the final as the newly-engaged Williams looks to better Steffi Graf's 22 Grand Slam singles titles by winning her seventh Australian crown.
That win sparked a memorable season for Kerber, who followed it up by claiming the US Open, where Williams crashed in the semi-finals and has barely played since.
Kerber gets her campaign started against Ukraine's Lesia Tsurenko on a Monday evening centre court clash.
But she has not had a good start to 2017, falling to Ukraine's Elina Svitolina in the Brisbane International quarter-finals, then slumping out in round two of the Sydney International to Russian teenager Darya Kasatkina.
"For me, I'm expecting the same as I was expecting the years before -- going out there trying my best, fighting till the last point," she said.
"This is always how I'm playing, how I am. This will not be changing."
- Konta on a high -
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Aside from Kerber, Polish world number three Agnieszka Radwanska, who lost to Williams in last year's semi-finals, Romanian pocket-rocket Simona Halep and Spain's Garbine Muguruza all pose a threat.
Konta, who made the semis last year and was named the WTA's most improved player for 2016, has blossomed and is encouraged by winning in Sydney.
Czech Republic's Pliskova is another dangerous floater but like Konta is taking nothing for granted despite her stellar early season efforts.
"I would definitely not take me as a favourite of this tournament," said the tall 24-year-old, who won the girl's singles title at Melbourne Park in 2010.
Several notable players are missing, including two-time Wimbledon champion Petra Kvitova who was injured by a knife-wielding intruder at her home in the Czech Republic last month.
World number eight Madison Keys is another absentee after minor wrist surgery.