The second-ranked Nadal plays left-handed, but he uses a two-handed backhand.
The 14-time major champion was hurt July 29 while practicing on his home island of Mallorca ahead of the North American hard-court circuit. The next day, Nadal announced he needed to wear a cast on his wrist for two to three weeks and would be sitting out tournaments in Toronto and Cincinnati.
The 28-year-old Spaniard also said at that time he expected to return for the U.S. Open.
Instead, he's the fourth man in the Open era, which began in 1968, to decline to try to defend his U.S. Open title. The others were Ken Rosewall in 1971, Pete Sampras in 2003 and Juan Martin del Potro in 2010. Del Potro also is out of this year's U.S. Open after wrist surgery in March.
Nadal is 44-8 with four titles in 2014, including his record ninth French Open trophy in June. He has not competed since losing in the fourth round of Wimbledon on July 1.
With Nadal sidelined, five-time U.S. Open champion Federer joins Djokovic as a favorite in New York even if there are questions about them.
Federer turned 33 this month, and it's been more than two years since he won one of his record 17 Grand Slam titles. But he is coming off a runner-up finish at Wimbledon last month and a hard-court title at the Cincinnati Masters on Sunday.
After beating David Ferrer 6-3, 1-6, 6-2 on Sunday, Federer declared: "My game's exactly where I want it to be."
Djokovic won Wimbledon to take the No. 1 ranking from Nadal, but had a rough time on hard courts, losing his second match in both Toronto and Cincinnati.
Still, Djokovic will be seeded No. 1 at the U.S. Open, and the third-ranked Federer is expected to rise one seeding spot to No. 2, so they could meet only in the final. The draw is Thursday.