The top-seeded Nadal joined a series of high seeds in the third round by winning his evening match at the Billie Jean King National Tennis Center.
No. 4 seed David Ferrer, sixth-seeded Andy Murray and No. 9 James Blake all advanced with second-round victories.
Ferrer, a semifinalist here last year, rallied to defeat Andreas Beck 4-6, 7-5, 6-3, 7-6 (7-5). Murray also had to work hard to get past Michael Llodra 6-4, 1-6, 7-5, 7-6 (9-7). Murray has never advanced past the round of 16 at the U.S. Open.
Blake was leading Steve Darcis 4-6, 6-3, 1-0 when the Belgian retired due to an injury.
Blake will take on Mardy Fish in the third round. Fish advanced with a 6-2, 3-6, 6-3, 6-4 victory over Paul-Henri Mathieu, serving 27 aces in the process.
Fish is making his ninth straight appearance at the U.S. Open and he will be playing in the third round for the first time.
Other winners in the men's draw included David Nalbandian, Stanislas Wawrinka and Gilles Simon.
Simon shocked Roger Federer at the recently-concluded Olympics.