Clinching a 6-2 7-6 7-5 victory over 39th-ranked Istomin, the French Open and Wimbledon champ now marches into the third round in his quest to capture his first US Open title.
"If I can win this tournament it would be a dream. But I'm five matches away. I don't think about winning this tournament right now," the 24-year-old Spaniard said after his victory over unseeded Istomin.
Nadal will next go head-on against Gilles Simon of France, who earlier defeated 29th seed Philipp Kohlschreiber of Germany.
"For me the goal is to try to improve my level, to play well (in) the next match, and we will see what happens next Sunday. For me it is not an obsession," Nadal added.