Isner, who was a quarter-finalist at Flushing Meadows last year, lost his serve early in the opening set but responded with two breaks of his own to edge ahead 6-3.
Both players held serve with supreme authority in set two, winning six service games apiece before Nieminen took the topsy-turvy tie-break 7-5.
Isner survived three break points on his way to claiming the third 6-4. He then comfortably sealed the victory by winning the fourth 6-3.
Isner hit a total of 69 winners, compared to his opponent's 28, and the American out-aced the Norwegian by 23 to five.