Fresh off soaring to within the cusp of the world's top 50 last season, O'Connell showed his class and resilience on Sunday to recover from two sets to one down and prevail 3-6 7-5 4-6 6-1 7-5 in a marathon encounter stretching almost four and a half hours.
Garin broke Alex de Minaur's heart in a fourth-round Wimbledon thriller 18 months ago but he couldn't break O'Connell's spirit as the one-time Pittwater boat cleaner finished with a wet sail.
The 29-year-old broke Garin five times in the last two sets in a performance O'Connell rated better than his second-round straight-sets win over 13th seed Diego Schwartzman at Melbourne Park in 2022.
"This one felt a lot better. Cristian has been an unbelievable player. He may even have been in the top 20 at one point," O'Connell said after saving Australia from a first-day wipe-out.
"Doing it over five sets, yeah, just feels a little bit better, even though it's tougher.
"It was more straightforward against Diego a couple of years ago but, yeah, that felt awesome out there.
"I'm feeling unreal. Amazing feeling. I've had so many good memories on that court, but I've just added another one."
O'Connell's reward is a date on Wednesday with American 16th seed Ben Shelton or Spanish former top-tenner Roberto Bautista-Agut.
"I've already had an ice bath. I'm going to have some treatment after this," he said of how he's preparing to back up after such a gruelling contest.
"Probably won't practice tomorrow. I'll get more treatment. Just do everything I can. Massage. Probably hit a little bit on Tuesday. Maybe I play doubles. I don't know."
O'Connell's epic win preceded a gut-wrenching five-set defeat for countryman Jason Kubler and losses for Dane Sweeny and Adam Walton on their main-draw debuts at the Open.
Hindered by a wrist issue, Kubler let a 4-2 fifth-set lead slip in a drama-charged 2-6 6-3 7-6 (7-3) 4-6 7-6 (10-8) loss to cramping Colombian Daniel Elahi Galan.
The match lasted a minute shy of five hours.
Sweeny won plenty of admirers by pushing No.22 seed Francisco Cerundolo to five tough sets in a memorable but ultimately losing grand slam debut.
Showing plenty of the never-say-die traits of his doppelganger Lleyton Hewitt, the world No.257 traded blows for the best part of three and a half hours before bowing out 3-6 6-3 6-4 2-6-6-2.
Cerundolo dominated the winner's count 57-20 but the 22-year-old Sweeny's counter-punching qualities kept him in the contest throughout.
The seeded Francisco Cerundolo had to work hard for his win against Dane Sweeny. (James Ross/AAP PHOTOS)
Wildcard Walton made an encouraging start before being overwhelmed by rising Italian star Matteo Arnaldi.
Playing just his second Tour-level match, the 24-year-old Walton served for the opening set at 6-5 but was unable to hold.
World No.41 Arnaldi took command in the tiebreak and then put his foot down to win 7-6 (7-5) 6-2 6-4.
The 22-year-old Arnaldi was a member of the victorious Italian Davis Cup team in 2023, beating Australia's Alexei Popyrin in the opening match of the finals.
He also reached the fourth round of last year's US Open before losing to Carlos Alcaraz.
Adam Walton started well before succumbing to Italian star Matteo Arnaldi. (James Ross/AAP PHOTOS)
Walton cut his teeth on the US college circuit from 2017-22 with the University of Tennessee, winning the 2021 NCAA doubles title.
O'Connell, Walton and Sweeny are among the 15 Australian men in the singles draw at Melbourne Park this year, the largest local contingent since 1998.
Australia's highest-ranked player, No.10 seed Alex de Minaur, has been handed a difficult first-round clash with 2016 Wimbledon finalist Milos Raonic on Monday night on Rod Laver Arena.
The big-serving Canadian has endured a wretched two-year run with injury but still shapes as a dangerous floater.
