Updated: September 16, 2012, 10:45 AM ETAssociated Press
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.
Even without Rafael Nadal, Spain, which will try to win its fourth title in five years, stretched its record home winning streak to 24 straight. It hasn't lost on clay since 1999.
Spain will play at the Czech Republic or Argentina in November's final.
Ferrer showed again he could fill the leadership void left by the injured Nadal, who has said he will scale back his Davis Cup availability after clinching last year's final title against Argentina.
"I'm very happy and this is a dream for me. Another Davis Cup final," said Ferrer, who has played a part in each of Spain's last three titles. "For me (it's) the best emotions, Davis Cup. I really want to enjoy this moment now."
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 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.
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.
Copyright 2012 by The Associated Press