Del Potro ended a 10-month injury lay-off with a 6-3 7-6 (7-4) victory over Ukraine's Sergiy Stakhovsky on Tuesday.
The former world number four, who defeated Australian Bernard Tomic in last year's final, had been sidelined since undergoing surgery on his troublesome wrist in February.
But the towering Argentinian made light work of Stakhovsky, booking his spot in the second round after one hour and 21 minutes on court at the Australian Open lead-up event.
"It was a great moment for me," Del Potro said. "I think I played well in my first match after 10 months. I served well. My forehand is still working out. So that's a good signal for the future. "
Del Potro added: "I've been at home for a long time; [it's been] really sad. To be honest, I didn't expect this moment to be early in the season. I'm so happy, so glad.
"I would like to share with a lot of people who were behind me last year, but all of them are in Argentina. So I will meet them once again very soon."
Del Potro started well, breaking early to open up a 3-1 lead en route to claiming the opening set.
The 26-year-old faced stiffer opposition in the second set, with Stakhovsky forcing a tie-break, but Del Potro withstood the challenge to earn a second-round showdown against top seed Fabio Fognini.
Tomic also made it through to the second round, blitzing Dutch qualifier Igor Sijsling 6-2 6-1.
Tomic - the 2013 champion - was on court for just 43 minutes as he secured a meeting with third-seeded German Philipp Kohlschreiber.
Seventh seed Jeremy Chardy was a 6-4 6-4 winner against Sam Querrey and will be joined in round two by Mikhail Kukushkin, Pablo Andujar, Vasek Pospisil and Viktor Troicki.
Kazakh qualifier Kukushkin saw off Denis Istomin 6-3 7-6 (7-1), Andujar disposed of qualifier Jarkko Nieminen 6-2 6-2, Pospisil overcame Andreas Seppi 6-3 7-6 (7-4) and Troicki surprised eighth-seed Martin Klizan 6-2 6-3.
Heavy rain in Sydney caused significant delays to later matches and when play resumed there was double disappointment for the home fans that had stuck around.
Nick Kyrgios returned from a back injury that saw him miss last week's Hopman Cup and put up a brave fight against Jerzy Janowicz before going down 6-1 6-7 (6-8) 7-6 (7-5).
Fellow Australian Sam Groth was also eliminated in three sets, as Gilles Muller prevailed 3-6 6-3 7-6 (8-6).