The gentle giant was felled 4-6 6-3 5-7 6-4 7-5 in the second round by Spain's Roberto Bautista in the early hours of Friday morning.
The fifth-seeded Argentine had shown signs that he might be returning to his best form with victory in the warm-up tournament in Sydney but succumbed in a three-hour 53-minute thriller on court two.
"He played a great match. It's tough when you play a very high level for four hours," the 25-year-old Del Potro told reporters.
Extreme heat kept the former U.S. Open champion and his 62nd-ranked opponent off court until 9.25pm local time and they treated the crowd to an exciting match in which they combined for 100 unforced errors and 125 winners.
Bautista went for his shots to win the latter count 72-53 and took his place in the third round at a grand slam tournament for the first time when the exhausted world number five netted.
Despite succumbing so early in the tournament, Del Potro did not seem too disheartened.
"I already won a tournament last week and that gives me confidence to improve my game," he said.
"This kind of match also helps me to learn something and I will try to take the positive things about this match...to improve my game."
(Reporting by Nick Mulvenney, additional writing by Pritha Sarkar, editing by Tony Jimenez)
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