Well, some would argue it was always the American's to lose, given she has won 21 grand slam titles and was by far the standout women's player in 2015. She came within two matches, of course, of achieving the rare calendar-year grand slam.
But after Sunday's play in Melbourne, none of the three players that downed Williams last year -- Belinda Bencic, Petra Kvitova and Roberta Vinci -- remain in the tournament, and the knee injury in early January that threw the world No. 1's Australian Open preparations for a loop appears to have settled nicely.
The 34-year-old cruised into the quarterfinals by beating Margarita Gasparyan 6-2 6-1 and set up a clash with Maria Sharapova in a matchup that is justifiably hyped but rarely delivers on the court.
It pits the world's richest female athlete, Sharapova, against Williams, who many would argue is the greatest women's tennis player the sport has ever witnessed.
The world's top men's player at the moment, meanwhile, Novak Djokovic, survived a five-set battle against French counterpuncher Gilles Simon despite making 100 unforced errors. The 10-time grand slam champion prevailed 6-3 6-7 (1-7) 6-4 4-6 6-3 in 4 1/2 hours.
Williams has won 17 straight matches against Sharapova, including last year's Australian Open final. Sharapova managed to make the second set close, taking proceedings to a tiebreak, but when they squared off in the Wimbledon semifinals months later the Russian was always playing catchup and exited in straight sets.
Sharapova defeated rising Swiss star Belinda Bencic 7-5 7-5 to advance to the last eight, playing the match ahead of Williams on Rod Laver Arena with the roof closed due to rain. The roof was opened for Williams' 55-minute work out.
The Russian enjoyed one of the best serving days of her life, harkening memories of her form prior to a career-threatening shoulder injury in 2008.
But a career-high 21 aces didn't seem to trouble Williams' coach, Patrick Mouratoglou, as he looked ahead to Tuesday.
"Okay, we'll see if she hits 21 aces against Serena," Mouratoglou told CNN. "I doubt it."
Although the Frenchman said "anything can happen in tennis" and "Serena can be in a terrible day and Maria can be in the best day of her life," his words and body language didn't suggest he expected a twist in the rivalry.
"I think for now that Maria did not find the solutions against Serena for a long time," he said.
"I don't know if they exist or not. The keys of the match I'm not going to say. But I think Serena has the keys."
This, however, might be a good omen for Sharapova: Last year in the Australian Open quarterfinals, Tomas Berdych ended a 17-match losing streak against Rafael Nadal.
Yet the slumping Nadal is at a different stage of his career than Williams.
"You're always trying to improve," Sharapova, a five-time grand slam winner, told reporters. "I got myself into the quarterfinal of a grand slam.
"There's no reason I shouldn't be looking to improve and to getting my game in a better position than any other previous round. It's only going to be tougher, especially against Serena."
Any insight from Sharapova's coach, Sven Groeneveld, wasn't possible since he is not allowed to speak to reporters without permission from Sharapova's longtime agent, Max Eisenbud. Eisenbud declined CNN's request.
But Roger Rasheed, who guided Sharapova's former boyfriend Grigor Dimitrov and Gael Monfils into the top-10, said Sharapova has to do something different. For one he said he'd throw caution to the wind in the first set. He'd tell Sharapova to change her strategy when returning. And he'd employ tactics that have nothing to do with hitting a forehand or backhand.
"I'd be deliberate about changing the way things look," Rasheed, a television analyst with host broadcaster Channel 7, told CNN.
"I'd do little things that actually need to rattle the cage because at the moment everything is in Serena's favor."
Sharapova hitting 21 more aces would help but like Mouratoglou, Rasheed said it could prove difficult because of their history.
"If she can serve that amount of aces," said Rasheed, before pausing, "a different opponent though. She looks down the other end and it's Serena so it's a different vision.
"The whole walk-on to the court is a different experience. She's been there lots of times but it's a different mentality.
"As strong as Maria is, it's a different mind that walks onto the court than in different matches."
A win for Sharapova would be sweeter than her Sugarpova candy.
Carla Suarez Navarro ended the run of home hope Daria Gavrilova 0-6 6-3 6-2, with the 10th-seeded Spaniard -- dealing with a knee injury -- next playing fourth seed Agnieszka Radwanska. Radwanska, victor at the year-end championships in November, rallied to fend off Anna-Lena Friedsam 6-7 (6-8) 6-1 7-5 in a thriller. Friedsam, 21, was in tears after suffering from leg cramps late in the decider.
Djokovic reached his 27th consecutive grand slam quarterfinal in the Open Era to tie Jimmy Connors for second -- Roger Federer heads the list with 36 -- but his display as afternoon turned into evening in Melbourne was nothing like his grand slam play of 2015.
A sluggish Djokovic went 0-for-11 on break points in the second set and he routinely misfired with his drop shot.
When a fan yelled out during Djokovic's post-match interview on court, "no more drop shots," the Serb replied: "I hate to say that but you are absolutely right."
What was Djokovic thinking after the fourth set?
"You don't want to know," was his reply.
Djokovic became agitated as the crowd heavily rooted for the 15th-ranked Simon -- who took part in a 71-shot rally with Gael Monfils at the Australian Open in 2013 -- but he blew open the fifth set by taking a 5-1 lead.
The 28-year-old will hope for a reversal of Sunday's form when he plays Kei Nishikori, who beat 2008 Australian Open finalist Jo-Wilfried Tsonga 6-4 6-2 6-4.
"Actually, it gives me great joy to know that I can't get worse than that, than what I played today," Djokovic later told reporters. "It doesn't concern me for the next one."
Djokovic, even with his blip, and Federer are expected to tangle in the semifinals.
The Swiss continued his tournament Sunday evening against friend David Goffin, crushing the Belgian 6-2 6-1 6-4. He awaits sixth-ranked Berdych in the quarterfinals. Berdych contested a five-setter against Roberto Bautista-Agut, 4-6 6-4 6-3 1-6 6-3.
Away from the court there was good news surrounding the health of Andy Murray's father-in-law, Nigel Sears, who collapsed Saturday
while he watched his pupil Ana Ivanovic at Rod Laver Arena.
A tournament statement said the 58-year-old was expected to be released from hospital Sunday and has been cleared to return home to the UK.
"I have been cleared to fly back to the UK in the next day or so," Sears said.