With the loss Ferrer earned the dubious distinction of becoming the first top 10 men's seed to be shown the exit while Simon moves on to face either big serving Croatian Marin Cilic, who beat South African Kevin Anderson 6-3 3-6 6-3 6-4.
A well-rested Ferrer, who reached the third round in a walkover after Australian Bernard Tomic withdrew with a hip injury, got off to a sluggish start but fought back to take the second.
But by the end of the nearly three-hour clash a distressed Ferrer was hunched over the courtside timing board between points dripping in sweat with the 26th seeded Simon finishing off the exhausted Spaniard on his third match point.
"David is always fighting until the end," said Simon, after earning just his second win in seven meetings with Ferrer. "We were 5-1 he destroyed me five times. I just stayed relax today and had nothing to lose.
"I had a good start and then you know how it is."
Elsewhere, Dominic Thiem continued to impress with a 6-4 6-2 6-3 victory over Spain's 19th seed Feliciano Lopez. The Austrian 20-year-old set up a clash with Czech sixth seed Tomas Berdych, a 6-3 6-2 6-4 winner of Teymurauz Gabashvili.
Bulgarian seventh seed Grigor Dimitrov, who's match was moved from the Arthur Ashe night schedule to the Grandstand arena after the early evening's thunder and lightning storm, overcame a shaky start to beat David Goffin 0-6 6-3 6-4 6-1.
Dimitrov will face 20th seed Gael Monfils in the fourth round after he was impressive in an all-French battle against 12th seeded Gilles Simon. Monfils triumphed 6-4 6-2 6-2 in one hour and 55 minutes.
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