Riding a 22-match winning streak, the American juggernaut arrives in Melbourne Park fit, fresh and ravenous for more grand slam success at a tournament where injuries and illness have robbed her of yet more silverware in the past three years.
Age has not wearied the 32-year-old, who after winning her second French Open crown last year became the oldest woman to win the US Open when she raised her 17th grand slam trophy at Flushing Meadows.
The winner at Melbourne Park in 2003, 2005, 2007, 2009 and 2010, another triumph would see Williams equal Martina Navratilova and Chris Evert's tally of 18 major titles and draw her closer to German great Steffi Graf's 22. Australian Margaret Court leads the all-time list with 24.
Williams's place in the tennis pantheon is assured but her coach Patrick Mouratoglou believes the American could secure a calendar grand slam, which would make her the third woman after Court in 1970 and Graf in 1988 to achieve the feat in the open era.
"Look at the level she plays at the moment," Mouratoglou told the BBC this week. "She's beaten all the top players many times, so you can aim that high."
In contrast to the men's tour, which has been blessed by the power struggles between Roger Federer, Rafa Nadal, Novak Djokovic and Andy Murray in recent seasons, the women's tour is crying out for a genuine challenger to Williams.
Azarenka underlined her toughness last year with an impressive title defence, beating China's Li Na in front of a hostile crowd in Rod Laver Arena.
The powerful Belarusian proved a worthy winner, after having weathered a storm of criticism for taking a prolonged medical time-out during a tense passage of play late in her semi-final against American Sloane Stephens.
Tellingly, Azarenka avoided Williams during both her runs to the Australian title, with the American eliminated after being hobbled by injuries.
Azarenka also dodged Williams at last year's Brisbane International in the lead up to Melbourne Park but there was no hiding at this year's warm-up where she was beaten in straight sets by the American in the final.
That match followed Williams's straight sets win over four-times grand slam champion Sharapova, her 14th in succession against the glamorous Russian.
Sharapova's shoulder problems ensured a disappointing 2013 in which she missed the U.S. Open and split with long-time coach Thomas Hogstedt.
After a surprising collaboration with American Jimmy Connors, which lasted only one tournament, the 26-year-old brings a new coach in Sven Groeneveld, a former mentor to Monica Seles and Ana Invanovic, and the satisfaction that she enters the tournament injury-free after Brisbane.
While a Williams win would seem virtually assured, the American, who faces Australian wildcard Ashleigh Barty in the first round, would be wary that the crackling energy of major tournaments often tears up the script.
Asia's first grand slam singles champion, former French Open winner Li would hardly count as unheralded but always looms as a threat on the blue courts of Melbourne Park, where she believes the venue's 'qi' - or 'air' - raises her game.
German Sabine Lisicki's fourth-round upset of Williams at Wimbledon last year was also a timely reminder that the majors can turn the most unfancied of players into warriors capable of humbling the world's best with one inspired hour.