Murray, who finished second here last year and was the second seed this year, was done in by 16th-seeded Croat Marin Cilic, 7-5, 6-2, 6-2.
Cilic, 20, saved two set points in the first set, then broke Murray's serve twice to go up 3-0 in the second set that he polished off with an ace. The third set was more of the same as Cilic broke the listless Scotsman in the first game.
Cilic produced 35-13 edge in winners and broke Murray's service five times without losing any en route to his first Grand Slam quarterfinal. It was his first win against a Top 3 player.
Del Potro, seeded sixth, easily ousted former No. 1 Spaniard Juan Carlos Ferrero in straight sets 6-3, 6-3, 6-3 in the fourth round at Ashe Stadium.
Del Potro, another 20-year-old who also reached the quarterfinals last year, will now face Cilic in the semifinals.