The second-seeded/world No. 2 Nadal dropped the first set against 18-year-old American Sam Querrey before rebounding for a 6-7 (5-7), 6-2, 6-3 decision in 2 hours, 2 minutes.
The Wimbledon runner-up and reigning two-time French Open champ, Nadal improved to 46-6 this season and rebounded from last week's third-round loss against Czech Tomas Berdych, in Toronto.
Up next for Nadal, 20, will be Korean Hyung-Taik Lee.
World No.1 Roger Federer also advanced Tuesday. The top-seeded Swiss Federer had a more difficult time than expected in getting past Thai Paradorn Srichaphan, 7-5, 6-4. After falling behind 5-3 in the opening set, Federer took the next four games to capture the opening set.
Federer is coming off his seventh title of the year Sunday in Toronto. Federer has a 55-match winning streak in North America since his last loss to Dominik Hrbaty in the first round here on August 3, 2004. That streak has brought Federer nine titles, including this tournament last year and the U.S. Open in 2004-05.
American Andy Roddick, 23, beat Italian Daniele Bracciali, 28, 6-7 (6-8), 7-6 (7-4), 7-6 (7-5) in a match that featured no breaks of serve.