Karlovic smashed 75 aces, an Australian Open record, and 84 games also set a new tiebreak-era mark for the tournament before he finally sealed it 6-7 (6/8), 3-6, 7-5, 6-2, 22-20.
Karlovic and Zeballos played for five hours and 15 minutes, one of the longest matches in Australian Open history, in an astonishing first-round encounter on Court 19.
But their efforts paled in comparison to John Isner's world-record win over Nicolas Mahut at Wimbledon in 2010, which lasted for 11 hours, five minutes and stretched to 183 games.
"Actually I was thinking about that other match, Isner against Mahut. I was hoping a little bit it could go this long so I could also have the record."
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The denouement, when it finally came, was almost comical as an exhausted Karlovic chipped a hopeful lob over Zeballos, only for the Argentine to send a wayward forehand rocketing out of the court.
Karlovic, 37, roared in delight and pranced around court as he completed the ironman comeback from two sets down against the deflated Zeballos.
"I had to also fight against him and against my own head, you know. So it was definitely really difficult."
- Race to recover -
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The match beat the Australian Open's previous tiebreak-era record of 83 games, set in Andy Roddick's defeat of Younes El Aynaoui in 2003.
But it stopped the clock short of the five hours, 53 minutes played by Novak Djokovic and Rafael Nadal in the men's singles final of 2012.
In 2009 Karlovic, who holds the record of more than 11,000 career aces, fired 78 aces in a Davis Cup match against the Czech Republic's Radek Stepanek -- and still lost.
He now faces a race to recover before his second round match in Melbourne on Thursday, against Australian wildcard Andrew Whittington.
"I don't know how I will recover. I have two days now. Tomorrow off. I will not even hit. I'm just going to do the ice bath, try to hit good, go to sleep early. Hopefully that will be enough," Karlovic said.