World No. 36 Frenchman Jeremy Chardy came out on fire against Del Potro, the world No. 7 and 2009 US Open champion, playing perhaps the match of his career with some incredible winners as he won in five sets, 6-3, 6-3, 6-7 (3), 3-6, 6-3.
Chardy, whose only other fourth round Grand Slam appearance was at Roland Garros in 2008, claimed by far his biggest scalp in one of the majors by playing the best tennis he likely has.
The 25-year-old came out on fire in the first two sets dropping just six games against the big Argentine, who had been in strong form so far this Australian summer.
Del Potro was never going to throw in the towel and was able to steady somewhat in the third set and get it into a tie-break, which he won seven points to three. He then cruised through the fourth winning it 6-3 to gather up all the momentum.
However, the Frenchman wasn’t done with yet and made sure that Del Potro is still yet to come back from being down two sets to love in his career. Chardy found his form of the first two sets again and won the deciding set 6-3.
Chardy played an outstanding match with an astounding 78 winners to Del Potro's 36, plus 20 aces to 13.
It was a philosophical Del Potro after the match conceding he was just beaten by a better man on the day.
"It's not a good result after coming back from two sets down, but Jeremy played really well in the fifth set and he deserved to win the match. He broke my serve and he was too good in the end so the tournament for me is over," Del Potro said.
"I will have to work hard now because the season has just started. I believe in my game and my serve, so I will keep working very hard on it now. The match was very tough because Jeremy played so strong for four hours.
"He served well and he made a lot of winners with the forehand and he was very good with his slices. In the end, when he had the chance to break me he did it and that was the key in the end. He played better than I did on the important points and took his chance to win the match."
Third-seed Murray continued on his merry way through the early rounds of the Australian Open with a straight-sets 6-3, 6-4, 7-5 win over world No. 110 Lithuanian Ricardas Berankis.
Murray has now beaten Robin Haase 6-4, 6-1, 6-4 and Joao Sousa 6-2, 6-2, 6-4 as well as the 6-3, 6-4, 7-5 win over Berankis to set up a fourth round clash with the winner of the battle of the French, Gilles Simon and Gael Monfils.
Another Frenchman, Tsonga had little trouble against Slovenian Blaz Kavcic winning in straight sets, 6-2, 6-1, 6-4.
Kavcic was clearly worn out from his marathon five-set second round clash with Australian James Duckworth, and Tsonga took full advantage with the seventh seed cruising into the fourth round to book a spot up against fellow countryman Gasquet.
Gasquet was in trouble early in his third round clash on Saturday against Croatian Ivan Dodig, but came back to win 4-6, 6-3, 7-6 (2), 6-0.
The ninth seed looked likely to be the first big name casualty of the day when Dodig was playing tremendously early, but the Frenchman wore him down and went through the fourth set virtually unchallenged after wearing his less experienced opponent down.
Italian Seppi was the other winner through to the fourth round on Saturday but it took him a tough five sets against fell big hitter and big man Croatian Marin Cilic.
Neither player was able to grab hold of any momentum with their serving and power games dominating right throughout the five sets, but it was the Italian who was able to win the fourth and fifth sets to advance to the fourth round to take on Del Potro's conqueror, Chardy.
The 21st seed Seppi just got the better of the 12 seeded Cilic in an entertaining affair as he reached a Grand Slam fourth round for just the second time in his career.
He last did it at Roland Garros last year after beating Fernando Verdasco in the third round, and then pushing world No. 1 Novak Djokovic all the way to five sets.