The No. 5 seed missed the end of last season and the beginning of this one with a right wrist injury and hadn't played on the main tour since last August in Montreal. He recently played two challenger-level events and his ranking has dropped to 27th after he was in the top five early in 2017.
Nishikori was a four-time champion of the Memphis Open, which moved to Long Island this year after four decades in Tennessee. He advanced to face Russia's Evgeny Donskoy, who beat Victor Estrella Burgos of the Dominican Republic 7-5, 6-1.
In the final match, Ernesto Escobedo came back to overcome fellow American Mackenzie McDonald 4-6, 6-3, 7-6 (5) in nearly two hours. He advanced to face top-seeded Kevin Anderson of South Africa, the U.S. Open runner-up who had a first-round bye.
No. 7 Steve Johnson of the U.S. was upset by Spain's Adrian Menendez-Maceiras 1-6, 6-3, 7-6 (7). Also, France's Jeremy Chardy edged Stefano Travaglia of Italy 4-6, 7-6 (1), 6-4; Russian Mikhail Youzhny outlasted Matthew Ebden of Australia 3-6, 6-3, 6-4; Radu Albot of Moldova beat American Bjorn Fratangelo 6-4, 6-3; and Peter Gojowczyk of Germany downed Slovenian Blaz Kavcic 6-4, 6-2.