Federer had looked vulnerable at this year's tournament with two five-set wins over unseeded opponents before finding his stride and cruising past 31st-seed Feliciano Lopez and German Philipp Kohlschreiber in straight sets to make the last eight.
Revenge should motivate the 36-year-old Federer, who had won an unprecedented five straight U.S. Open titles before losing to Del Potro in a marathon five-setter in 2009.
The Swiss has not won the U.S. Open since.
While world number three Federer is hugely popular with the New York crowd, the 24th seeded Del Potro can count on support from the legions of Argentines that have packed into Flushing Meadows this week to urge on their beloved "Delpo."
Del Potro gave them plenty to cheer on Monday when he recovered from two sets down and saved two match points in the fourth to beat Austrian sixth seed Dominic Thiem in a classic.
World number one Rafael Nadal or 19-year-old Russian Andrey Rublev will await the winner in the semis on Friday.
(Reporting by Rory Carroll; editing by Ken Ferris)
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