The 6-foot-9 American got past the Ukrainian qualifier 7-6 (7-3), 4-6, 6-3 to begin his title defense at Newport, R.I., where he beat Belgian Olivier Rochus in last year's grass-court finale.
His next opponent will be France's Nicolas Mahut. Isner and Mahut were involved in an epic, 11-hour-long opening-round Wimbledon match two years ago, which Isner won.
Also Tuesday, former world No. 1 Lleyton Hewitt needed just 49 minutes to dispatch Canadian Vasek Pospisil 6-1, 6-1.
Among the other winners at Newport were second-seeded Japanese Kei Nishikori, unseeded Americans Sam Querrey and Rajeev Ram, and third-seeded Canadian Milos Raonic.
Fourth-seeded Denis Istomin of Uzbekistan lost to American qualifier Tim Smyczek 6-3, 6-3 and eighth-seeded Gilles Muller of Luxembourg was upended by South African qualifier Izak Van der Merwe 7-6 (7-5), 6-7 (3-7), 6-4.