"I was a little lucky to win in straight sets," Nadal said. "He was a very difficult player to play. He played very fast."
Li's elimination marked a second round of U.S. Open without a reigning Grand Slam singles champion remaining, just the first since 1971.
On Monday, the Wimbledon champion, Petra Kvitova from Czech Republic, also made an early exit.
Caroline Wozniacki, the women's world No. 1 demolished unseeded Spaniard Nuria Llagostera Vives 6-3 6-1.
No. 4 Victoria Azarenka wasted little time in dispatching Johanna Larsson of Sweden 6-1, 6-3.
In men's draw, fifth-seeded David Ferrer rallied from a set down to beat 78th-ranked Igor Andreev, who committed 53 unforced errors.
The Spaniard won 2-6, 6-3, 6-0, 6-4. He hasn't lost in the first round at a major tournament since 2005. Ferrer had 14 unforced errors in dropping the first set, then had only 24 the rest of the way.
Jo-Wilfried Tsonga of France, the 11th seed, went through Lu Yen-Hsun of Chinese Taipei, 6-4, 6-4, 6-4, while 19th-seed Spaniard Fernando Verdasco fought back from a set down, dismissing Jarkko Nieminen of Finland, 3-6, 6-4, 6-1, 6-4.
Other seeds progressed were 17th-seeded Jurgen Melzer of Austria, beating Eric Prodon of France, 6-2, 7-6(4), 6-2; 30th-seeded Ivan Ljubicic of Croatia, dispatching Blaz Kavcic of Slovenia, 7-6(5), 3-6, 6-1, 7-5 and 14th-seeded Swiss Stanislas Wawrinka, who rallied past Maximo Gonzalez of Argentina 3-6, 6-4, 6-1, 6-3.
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