The fifth seed broke three times and held serve throughout to claim a solid 6-4 6-4 6-4 victory, setting up a clash with Croatian third seed Marin Cilic, an opponent he knows well having beaten him in 10 of their 12 meetings.
Against American Isner on Court Suzanne Lenglen, Del Potro, who is also one of the crowd darlings at the U.S. Open where he won his only Grand Slam title in 2009, kept hearing an American fan sing 'USA, USA'.
"I love playing here in the USA, USA!," he joked on court.
He then sang 'Allez Les Bleus', a song chanted by French team sports fans, which triggered loud applause from the local fans.
"There was this lady singing all the time 'USA, USA', but we are in France so since I know the (French) song I went for it," Del Potro, who is regarded as one of the biggest threats to 10-time champion Rafa Nadal at Roland Garros, told reporters.
"I returned very well, it was the key to the match and I broke three times, I also played well on the important points," said Del Potro, who throughout the match heard parts of the crowd chant 'USA, USA!"
"I have good fans in every tournament and I like my connection with them, and French fans know a lot about tennis," he added.
With no French player left in the draw, Del Potro could be aiming to become their favourite.
"It is so special to get to the quarter-finals here, I'm having great days in Paris and I'd like to stay a few more days," he said.
On Wednesday, he will take on another big server in Cilic, an opponent he has not lost against since 2011.
"We have played some great matches in the past and I know it is going to be tough," he said.
"I will try to play a similar match but he has other weapons (than Isner), he has good shots from the baseline and good shots down the line."
(Reporting by Julien Pretot; Editing by Ed Osmond)
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