The Argentine, who stands 13cm shorter than his opponent, took a little off his own serve to cope with the blustery conditions on the outdoor hardcourt. He held serve easily throughout and one break in each set was enough, clinching victory when Opelka sent a service return long.
Opelka won his first career title at the New York Open on Sunday but was nowhere near his best against Del Potro and looked particularly vulnerable on his second serve.
Next up for Del Potro in the quarter-finals on Friday is unseeded American Mackenzie McDonald, who beat Spaniard Guillermo Garcia-Lopez 7-5 6-4.
Also on Thursday, American fourth seed Steve Johnson beat Italian Paolo Lorenzi 7-5 7-5 and Radu Albot of Moldova beat Nick Kyrgios 6-2 3-6 6-3.
Australian Kyrgios raised some eyebrows with his antics during the match, and looked to have had a verbal exchange with a spectator during a changeover.
"There was a lot going through the mind of Nick Kyrgios," said Tennis Channel commentator Mark Knowles, a former world number one doubles player.
"He had the sidewinder serve, the chip forehand, he threw his racket up in the air, he had some conversations with the crowd, some dancing going on. Didn't seem like he was that focussed on his tennis today."
(Reporting by Andrew Both in Cary, North Carolina; Editing by Peter Rutherford)
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