Both won three majors, with Williams coming within two victories of becoming the first player since Steffi Graf in 1988 to achieve the calendar year grand slam. Djokovic trumped Williams, however, by playing in all four grand slam finals.
Here are five questions leading into Melbourne. We'll get the answers in two weeks.
Haven't we been here before with Serena Williams? Perhaps at the 2015 French Open?
The world No. 1, struck by a virus that she said at one stage made her "collapse," nonetheless battled her way to the crown at Roland Garros in June. Five of her seven matches on the red clay in Paris extended to three sets.
In the past, Williams has overcome injuries and a life-threatening illness to amass 21 grand slam singles titles.
It looks like the American will again need to compete at a major event without being fully healthy.
She retired from her opening match at the Hopman Cup in Perth due to a knee injury in the first week of January and then withdrew from the tournament altogether. The knee was one of the reasons, Williams said, she didn't contest another match in 2015 after losing in the U.S. Open semifinals to Roberta Vinci in September.
The crafty Italian foiled Williams' quest
to land all four majors in one season, but the 34-year-old still has much to play for Down Under -- retaining the title would put her equal with Graf's Open Era record tally of grand slams.
Williams could be in for a tricky opening, as she was drawn against one of the hardest hitters on the tour, Camila Giorgi. Ranked 35th, the Italian just missed out on a seeding.
Can anyone stop 'stratospheric' Djokovic?
Rafael Nadal lavished high praise on the world No. 1 after he was crushed by the Serb 6-1 6-2 in last week's final of the Qatar Open.
He even used the term "stratospheric" to describe Djokovic's level.
"I know nobody playing tennis like this, ever," Nadal told reporters.
One can understand why the Spaniard made such a bold comment: Djokovic has claimed 12 consecutive sets versus the 14-time grand slam champion on hard courts.
Other rivals have had greater success against Djokovic, either downing him or making things close.
Stan Wawrinka defeated him in the French Open final, denying him a collection of grand slam titles; Andy Murray had his opportunity in last year's Australian Open final; Roger Federer went 4-for-23 on break points in losing the U.S. Open final, and the Swiss also stretched Djokovic to four more sets at Wimbledon.
Yet Djokovic won all the big points, and has won 45 of his last 51 matches against top-10 opposition.
The Australian Open, too, is Djokovic's most successful major, accounting for half of his overall tally of 10.
Will Nadal pose a threat?
Federer owns a men's record 17 grand slam titles, but how many more would the 34-year-old possess if he didn't have to face Nadal? Similarly, how many majors would Nadal own if Djokovic was out of the way?
Seeing Djokovic on the other side of the net is, as the numbers tell us, bad news for Nadal.
But what if he didn't have to tangle with the 28-year-old? Then one could argue he is the man to beat.
Nadal's 2015 will be remembered for what he failed to win
-- no majors for the first time since 2004 -- but the fifth-ranked Mallorcan ended the campaign in positive fashion, making finals in Beijing and Basel then reaching the semis at the year-end championships before losing to Djokovic.
Those who have called for Nadal to lessen his spin-heavy game and hit the ball flatter will be pleased with what they are seeing, as those changes are seemingly being made. He is, too, positioning himself more aggressively on the baseline.
If he is to succeed at the Australian Open, Nadal will have to do it the hard way. He was placed in a quarter with several heavy hitters, including 2014 Australian Open champ Stan Wawrinka. Nadal begins against Fernando Verdasco -- who has beaten his compatriot in two of their past three encounters.
The two also played one of the most memorable matches in recent Australian Open history when Nadal edged Verdasco in roughly five hours in the 2009 semifinals.
The site of some of Nadal's most painful losses, could the Australian Open -- which he won in 2009 -- this year truly mark his revival?
Could Azarenka be the women's favorite?
While Williams is worrying about her knee, Victoria Azarenka appears fully healthy and ready to make a charge for a third title to add to those in 2012 and 2013.
Azarenka knows about injuries herself, plummeting in the rankings after a foot injury forced the Belorussian to sit out much of 2014.
Though she was still hampered physically in 2015, the former world No. 1 showed her class by almost defeating Williams on clay at the Madrid Open and the French Open. Her match with Williams in the Wimbledon quarterfinals
was considered one of the best of 2015.
Azarenka started 2016 impeccably, cruising to the title at a warmup in Brisbane by dropping a mere 17 games in five matches.
Will Murray stick around if his wife gives birth?
Murray's grand slam drought now sits at two and a half years, and during that time Wawrinka has matched his tally of two.
He is thus keen to end the skid, and doing so in Melbourne might be sweeter for the Scot since he has lost four finals at the Australian Open -- three to Djokovic.
In last year's title match, Djokovic appeared to be in trouble against Murray at the start of the third set but recovered to triumph in the fourth.
However, this year Murray has other distractions -- the world No. 2 said he would fly home if his wife Kim Sears gives birth during the tournament (she is due with their first child the second week of February).
"We spoke about it and chatted and obviously it would be disappointing if I was to get to that that position and not be able to play in the final," Murray told Australian television during the Hopman Cup.
"But I also said that I think I would be way more disappointed winning the Australian Open and missing the birth of the child.
"It was actually quite an easy decision in the end. Hopefully it doesn't come to that."
Murray is soon to become the third dad among tennis' "Big Four." Nadal is the lone member unmarried and without children.