Playing for the first time in 11 months after undergoing surgery to his left wrist, the Argentine beat Ukraine's Sergiy Stakhovsky 6-3 7-6(4).
"It's time to get back on the train again," del Potro told reporters. "This tournament is very special to me."
Del Potro won the Sydney International last year and is among dozens of competing players fine-tuning their preparations for the Australian Open, starting on Monday.
Romania's Simona Halep was among the high-profile entrants but she pulled out on Tuesday, saying she was suffering from gastroenteritis.
The world number three told organisers she was unable to take her place after falling ill in China, where she won the Shenzhen Open.
"During the tournament in China I got this problem in my stomach," she said. "I didn't play for three days. I was waiting until today to see if I was ready to play again, but I feel like I cannot play.
"It's tough to play a tournament like this so unfortunately I decided to withdraw."
Halep, runner-up at last year's French Open, said she expected to recover in time for the Australian Open, where she is among the favourites.
"You never know with the stomach, but hopefully in two or three days I'll be ready to play again," she said.
"Right now I just need to think about recovering, then I will worry about matches later."
Halep was the second big name to pull out of Sydney in the last two days. On Monday, U.S. Open runner-up Caroline Wozniacki withdrew due to a wrist injury after reaching the final of the Auckland Classic on Saturday.
Britain's Heather Watson upset American Sloane Stephens 6-3 6-1 at the Hobart International on Tuesday, another of the final warm-up events taking place before the first grand slam of 2015.
In New Zealand, the Auckland Open lost two more seeds when Santiago Giraldo and Guillermo Garcia-Lopez both lost.
Heavy rain washed out the entire first day's play at the Kooyong Classic, an eight-man exhibition event in suburban Melbourne, featuring Japan's Kei Nishikori.
(Reporting by Julian Linden; Editing by Peter Rutherford/Sudipto Ganguly)
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