Their triumphs might have been separated by almost a decade, but both players are former champions at Flushing Meadows and it was the 32-year-old former world No. 1 Australian who prevailed in four hours over the No. 6 seed, 6-4, 5-7, 3-6, 7-6 (2), 6-1.
Amazingly, it is the first time that Hewitt has beaten a player at the US Open who has been ranked inside the world's top 10 since he won the 2001 championship beating Pete Sampras in the final.
Hewitt started tremendously winning the first set 6-4 and then he was serving for the second at 5-4, but he coughed up his advantage and the Argentine big hitter started to find his range late in that second set.
That saw Del Potro claim the last three games of the second set and then win the third 6-3 but Hewitt again found something in the fourth set. He was again serving for the set before Del Potro broke him back to force a tie-break, but Hewitt dominated that seven points to two.
Remarkably despite Del Potro's big-hitting game, Hewitt cruised through the fifth set winning it 6-1 and recording one his most memorable victories in years.
For Hewitt, he was just excited to be back out on Arthur Ashe Stadium again and to be playing such a quality opponent, and to get a win shows just why he continues to work so hard to be able to still play the game.
"I was pumped up when I won my first round match because it meant I was playing a past champion here and great player Del Potro so there might be an opportunity to play on Arthur Ashe," Hewitt said.
"I don’t know how long I can keep playing so I was just hanging to get out here to play on this court again and try to put on a great show.
"A couple of years ago when I had my foot surgeries I didn’t know if I was going to play tennis again so to now be out here competing it's a hell of a lot of fun. I cherish every match I get out here at this point of my career and this is why I still play – to have moments like this.
"Sometimes playing the smaller tournaments they are hard to get up for, but there's nothing hard about getting up when you play out here, that's for sure.
Hewitt is now gearing up for his third round match-up with little known Russian Evgeny Donskoy who has beaten Austrian Jurgen Melzer and German Peter Gojowczyk in the first two rounds.
Other men's winners on the fifth day included Novak Djokovic, Tomas Berdych, Andy Murray, Tommy Haas, Marcos Baghdatis, Julien Benneteau, Andreas Seppi and Stanislas Wawrinka.
World No. 1 Djokovic had a tough opening set against Benjamin Becker, but the Serb eventually got on top of the German to come away with the 7-6 (2), 6-2, 6-2 victory.
Djokovic will now face Portugal's Joao Sousa in the third round after he beat Finish veteran Jarkko Nieminen 1-6, 6-3, 3-6, 6-3, 6-4 in another five-set second round battle.
World No. 5 Berdych is still hunting for his first Grand Slam title and is through to the third round after beating American Denis Kudla 7-6 (3), 7-6 (3), 6-3.
That sets up a tricky third round match-up for the Czech against Frenchman Benneteau who beat compatriot Jeremy Chardy 6-4, 6-3, 6-4 on Friday.
World No. 3 Murray didn’t have it all his own way against Argentine Leonardo Mayer, but ended up prevailing in four sets, 7-5, 6-1, 3-6, 6-1.
That now sees Murray set up a clash with another Mayer in the third round, Germany's Florian after he advanced by beating American Donald Young 7-5, 6-3, 6-4.
German veteran and No. 12 seed Haas had his moments of frustration against Chinese Taipei's Yen-Hsun Lu, but was still able to win in straight-sets 6-3, 6-4, 7-6 (3) to set up a third round clash with Russian 21nd-seed Mikhail Youzhny.
Youzhny won through to the third round with an impressive straight-sets win over Ukrainian Alex Dolgopolov, 7-5, 6-1, 6-3.
There was another five-setter between Marcel Granollers and American Rajeev Ram with the Spaniard Granollers winning 3-6, 4-6, 6-2, 6-3, 7-5 showing tremendous heart to come back from two sets to love down.
Granollers will now face American Tim Smyczek in the third round after he also won in five-sets over Russian Alex Bogomolov Jr, 3-6, 7-6 (6), 2-6, 6-4, 6-4.
Perhaps the most emphatic performance of the day came from Cyprus veteran Baghdatis. He thumped South African No. 17 seed Kevin Anderson 6-2, 6-2, 6-2.
The popular Baghdatis will now take on Swiss No. 9 seed Wawrinka in a tremendous third round contest.
Wawrinka won through with a terrific and hard fought straight-sets win over James Blake's conqueror, Ivo Karlovic 7-5, 7-6 (8), 6-4.
Italian Seppi had a hard time against Indian Somdev Devvarman, but he still won in three-sets 7-6 (8), 6-4, 7-5.
Seppi now next plays Uzbekistan's Denis Istomin in the third round after he beat German Tobias Kamke on Friday, 6-4, 6-2, 6-2.
Day 6 men's action sees Rafael Nadal in action on Arthur Ashe Stadium up against Ivan Dodig with Roger Federer then playing at night up against Frenchman Adrian Mannarino.
Louis Armstrong Stadium will host John Isner up against Philipp Kohlschreiber and then Tommy Robredo playing Daniel Evans.
In other matches of note, David Ferrer plays Mikhail Kukushkin, Janko Tipsarevic takes on Jack Sock, Feliciano Lopez battles Milos Raonic and Richard Gasquet faces Dmitry Tursunov.