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Nadal, trying for his second Indian Wells title in three years, rolled to a 6-2, 6-4 victory over Juan Martin del Potro.
No. 2 Roger Federer, who won the title for three consecutive years from 2004-06, faces No. 4 Andy Murray in the other semifinal.
Meanwhile, defending champion Ana Ivanovic of Serbia and Russia's Vera Zvonareva earned spots in the women's final.
Fifth-seeded Ivanovic defeated Anastasia Pavlyuchenkova 6-2, 6-3, while fourth-seeded Zvonareva beat Victoria Azarenka 6-3, 6-3.
Seventh-seeded Roddick's game was solid all-around against third-seeded Djokovic. The error-prone Serbian made 30 unforced errors, 18 more than his American opponent.
The semifinals appearance will be Roddick's third at Indian Wells. He lost to Lleyton Hewitt in 2005 and to Nadal in 2007.
Djokovic was extremely disappointed with his effort.
"It's just one of those days when you really don't feel comfortable on the court," he said. "I just didn't have any momentum - no feel for the ball, no movement. Just no solutions. It was all me making an incredible amount of unforced errors.
"This was one of the worst matches, certainly, I played."
Nadal covered the court extremely well in his win over sixth-seeded del Potro, keeping the ball in play even when the Argentine had him racing from side to side. Often, Nadal would be on the run and slash a winner crosscourt or down the line. He hit 25 winners, 13 with his forehand.
He has won four of six career meetings against Roddick, figures he's in for a difficult test in their semifinal. "He's playing very well. He started the season very well, semifinals in Australia. He played the final in Doha, too, and he won in Memphis," Nadal said. "It's going to be a really tough match."
Ivanovic, 21, dominated Pavlyuchenkova, a 17-year-old schoolgirl from Moscow who had upset No. 3 Jelena Jankovic and No. 10 Agnieszka Radwanska on the way to her first WTA semifinal. Pavlyuchenkova came in ranked No. 42.
"I was really happy with my performance," Ivanovic said. "She's not an easy opponent; she doesn't give you much rhythm."
The reigning French Open champion who held the No. 1 spot twice last year, seventh-ranked Ivanovic is going for her ninth tour title.
Zvonareva broke eighth-seeded Azarenka in the sixth game for the first set, and went up 2-0 in the second. The Russian saved all five break points she faced.
The 19-year-old Azarenka of Belarus lost for only the second time in 19 matches this year. Her run here, including a defeat of top-seeded Dinara Safina, will move her into the top 10 for the first time.
Zvonareva and Azarenka will be on the same side in the doubles final against Gisela Dulko and Shahar Peer. Lindsay Davenport was the last woman to win the Indian Wells singles and doubles titles, in 2000.