Captain Patrick McEnroe will also go with the world's top-ranked doubles team of brothers Bob and Mike Bryan in the best-of-five event in Winston-Salem, N.C.
The eighth Davis Cup meeting between the countries could include four of the top eight players in the rankings. Spain, which will announce its team Monday, is expected to have No. 2 Nadal and either No. 6 Tommy Robredo or No. 14 David Ferrer. Roddick is No. 3 and Blake is No. 8.
"If we play our best and we have the home court and the home crowd, we feel pretty good about our chances," McEnroe said. "We realize we'll have to play well."
The U.S.-Spain winner will face Sweden or Argentina in the semifinals Sept. 21-23.
McEnroe said Mardy Fish will serve as an emergency backup, and 17-year-old Donald Young will be a practice partner leading to the April 6-8 matches.
The U.S., which hasn't won the Davis Cup since 1995, beat the Czech Republic 4-1 in the first round last month, with Roddick winning the decisive match.
The U.S. Tennis Association picked Winston-Salem before Spain beat Switzerland 3-2 in the first round. So instead of grass, where Nadal had struggled until reaching the Wimbledon final last year, the competition will be held on a surface suited to Roddick's big serve and Blake's speed.
"We're looking for a court that is relatively quick and preferably one where the ball doesn't bounce particularly high," said McEnroe, who has been testing surfaces this week. "We realize that Nadal has proved he can basically play on anything, but we're trying to make the court more to our advantage."
Nadal is 2-1 against Roddick, including a clay-court win on the first day of the 2004 Davis Cup final, won by Spain. Nadal also beat Roddick 6-4, 6-3 Saturday in the semifinals of the Pacific Life Open in Indian Wells, Calif. Nadal, the two-time defending French Open champion, beat Novak Djokovic in straight sets Sunday for his first title in 13 tournaments.
"Nadal was playing great and the ball was jumping off the court out there," McEnroe said.
Roddick, 22-9 in the Davis Cup, lost both his matches last year in a semifinal loss to Russia.
Blake is 14-6 this year with one title and has beaten Nadal three times since 2005. But Blake has struggled of late and has lost four of his past five Davis Cup matches.
"I think he's been getting a little negative when he's been on the court, arguing with umpires and getting a little angry," McEnroe said. "He doesn't play well when he's angry."
"Obviously, it will be Blake against Nadal on the opening day," McEnroe added. "He has to go out there and play well."