Ferrer beat Isner 6-7 (3), 6-3, 6-4, 6-2 on Sunday to give the five-time champions an insurmountable 3-1 lead and a shot at a fourth title in five years. They'll face the Czech Republic on the road in the final.
Helped by Isner's 70 unforced errors, the fifth-ranked Ferrer rallied to stay unbeaten on clay in the competition with his 16th straight win.
Isner was left slamming his racket in frustration.
"Spain is the high water mark in the Davis Cup in the last 15 years. We always knew it was going to be close," U.S. captain Jim Courier said. "They have great individual players, great depth and great passion for Davis Cup. It's not rocket science. You have great ingredients and you have to blend them together, and they do a great job."
Ferrer and Nadal had both said they would scale back Davis Cup availability after helping clinch last year's final title against Argentina. While Nadal has since been limited by injury, Ferrer decided to return to make this his team now.
"This is the competition in which I have felt the most emotions in. I'm a team player," said Ferrer, who has played a part in each of Spain's last three titles. "I don't know how much longer my career will last, so I want to do my best possible in the Davis Cup. (Spain captain) Alex Corretja motivated me to play this season."
Spain stretched its record home winning streak to 24 straight, and it hasn't lost on clay for 26 series. Its last clay loss was in 1999.
And, just like in 2008, it did it without Nadal.
Isner had more than twice as many unforced errors as Ferrer at the near capacity 15,000-seat venue on the Asturian coast. He looked little like the player who beat Roger Federer in Switzerland in the competition earlier this year.
"The Spanish team was just too good," Isner said. "They won the important points, and it's a bit discouraging for me because I wanted to contribute like I did in the first two ties, and that's a credit to (Nicolas) Almagro and Ferrer, who got two of their points from me."
The American started well, ripping several of his 28 forehand winners past a tentative Ferrer, who stuck to the baseline. A pair of his 16 aces helped secure the lead when Ferrer's forehand sailed long in the first-set tiebreaker.
Isner's momentum came undone quickly, however. He started struggling with his forehand, and that helped Ferrer, who saved four of the six break points he faced, draw even and find his rhythm.
Isner was coming apart as his serve lost pace -- it clocked 143 mph in the first set. Ferrer earned triple break point in the seventh game of the third set, and the 10th-ranked American hit a forehand long to be broken. Later, Isner dropped his racket to the ground and kicked it before Ferrer moved one set from victory.
"I was going to fight, but in the fourth set he got on a bit of a roll," Isner said. "I don't think I got any free points on my serve; he returned my serve great in that fourth set, and he was playing with a lot of confidence."
Isner's frustration carried into the fourth set as he threw his racket to the ground and kicked it again as Ferrer broke to go up 2-1.
While the Bryan brothers clinched Saturday's doubles point, the U.S. has still only once recovered from a 0-2 deficit -- in 1934.