A bumper second day at Melbourne Park sees three-time finalist Daniil Medvedev, home hope Alex de Minaur and fourth seed Amanda Anisimova also enter the fray.
The 38-year-old Serbian great Djokovic faces Spain’s 71st-ranked Pedro Martinez on the final match of the day on Rod Laver Arena.
A former world number one, now ranked four, Djokovic is the undisputed king of Melbourne’s hard courts, having won a record 10 Australian Open crowns.
He has won 24 major titles, equal for the most ever with Australia’s Margaret Court, but a 25th has remained agonisingly out of reach.
With Carlos Alcaraz and Jannik Sinner now dominant, Djokovic’s last Grand Slam victory came at the US Open in 2023.
Despite age and injury catching up with him, Djokovic said on the eve of his favourite tournament: “I know that when I’m healthy, when I’m able to put all the pieces of the puzzle together on a given day, I feel like I can beat anybody”.
He added: “I like my chances always in any tournament, particularly here”.
Russia’s 11th-seeded Medvedev, runner-up in 2021, 2022 and 2024, warmed up for Melbourne with victory in Brisbane and believes he could be hard to beat.
“I know that when I’m playing good there are not that many players that can beat me easily or at all,” he said.
He meets Jesper de Jong of the Netherlands.
Australia’s De Minaur, the sixth seed, will have the Rod Laver Arena crowd roaring him on against 113th-ranked Mackenzie McDonald of the United States.
De Minaur has never gone beyond the quarter-finals at a Grand Slam.
Title contenders state case
The 21-year-old American Gauff opens proceedings on Rod Laver Arena against Uzbekistan’s Kamilla Rakhimova.
The third seed won the US Open in 2023 and French Open last year, but her best performance at the first Grand Slam of the year is the semi-finals.
Another firm contender for the women’s title is Poland’s Swiatek, the second seed, who has also never gone beyond the last four in Melbourne.
Like Alcaraz, Swiatek is pursuing a career Grand Slam of all four major titles, having triumphed previously at Wimbledon, the US Open and French Open.
Swiatek plays Chinese qualifier Yuan Yue while the American Anisimova, runner-up last year at Wimbledon and the US Open, meets Switzerland’s Simona Waltert.
The 18-year-old Russian talent Mirra Andreeva – fresh from winning her fourth title – takes on Croatia’s Donna Vekic.
Other notable names in action include the 2014 champion Stan Wawrinka, who was handed a wildcard aged 40 in his last Australian Open before retirement.
Top-10 seeds Felix Auger-Aliassime of Canada and Jessica Pegula of the United States also feature on day two.