World number five Ferrer had to fight from a set down on the clay in the northern Spanish coastal city, coming through 6-7 6-3 6-4 6-2 against the 10th-ranked Isner in exactly three hours for his 16th victory in 16 singles rubbers on clay.
"It was a very tough, very difficult tie but we are really happy as we are in another Davis Cup final, something that is extremely hard to achieve," Ferrer said.
"Now we just need to enjoy it and rest and prepare for the final," added the 30-year-old, who has won five titles this year and reached the US Open semi-finals this month.
Spain will play away against Czech Republic, whom they beat in the 2011 and 2009 finals respectively, in November's title clash.
Ferrer said the Spanish were hoping talisman Rafa Nadal, who has not played since Wimbledon, would have shrugged off a knee injury in time to feature.
"Spanish tennis is blessed with very good players, led by Rafa Nadal, and we hope he recovers soon because he is fundamental for us," he added.
Isner told Spanish TV before the match Ferrer was probably his favourite player on the tour for his work ethic and fighting spirit but it was the American who battled back from a break down to take the opening set 7-3 in the tiebreak.
One US fan held up a card counting each of Isner's booming aces - he powered down 16 in the match to Ferrer's five - but the American also made 70 unforced errors to Ferrer's 32 and he was visibly tiring as his challenge faded in the fourth set.
He saved a match point on his serve to stay in the match but it was merely delaying the inevitable as Ferrer sealed victory the next game when Isner went wide with a limp backhand.
Ferrer flung his racket into the crowd before he, Isner and captains Alex Corretja and Jim Courier shook hands at the net. Shortly after it was announced that Nicolas Almagro and Sam Querrey would not contest the dead final rubber.
Top-ranked US pair Bob and Mike Bryan had kept their team's hopes of upsetting the Spanish alive when they fought off a brave challenge from Marcel Granollers and Marc Lopez to win their doubles on Saturday.
Ferrer and Almagro beat Querrey and Isner respectively in Friday's singles.
Favourites to win a fourth title in five years, Spain's latest success extended their unbeaten run at home to 24 ties dating back to 1999 when they lost 3-2 to Brazil in Lerida.
The US are the most successful Davis Cup nation with 32 titles, while Spain have dominated the competition over the past decade, with four titles since their first one in 2000.
Czech Republic took an unassailable 3-1 lead over Argentina with Tomas Berdych's comfortable 6-3 6-3 6-4 win over Carlos Berlocq to secure their place opposite Spain.
Argentina's chances of reaching a second consecutive final had diminished on Saturday when world number eight Juan Martin del Potro pulled out of Sunday's first reverse singles against Berdych with a left wrist injury.
Del Potro had won the first point of the semi-final tie at Parque Roca when he beat Radek Stepanek in Friday's opening singles before world number six Berdych beat Juan Monaco in five sets.
Del Potro, however, was forced to pull out after aggravating a problem for which his doctor had recommended a fortnight's rest after last week's US Open.
The Czechs, who lost the 2009 final to Spain in Barcelona, will be at home this time. They have won the trophy once as Czechoslovakia in 1980.
Berdych was never really in danger against the 45th-ranked Berlocq, who had been picked for his maiden Davis Cup tie at 29 as Eduardo Schwank's doubles partner in the absence of the injured David Nalbandian. Berdych and Stepanek won the doubles in three sets on Saturday to put the Czechs 2-1 up.
Berdych seemed to have another gear he could call on if Berlocq managed to turn up the heat, the gear he resorted to when he was 2-1 and 4-1 down in the fourth set to Monaco on Friday.
Berlocq, comfortable on clay, fed on the rowdy home crowd support to trouble Berdych with timely attacks at the net but was more often on the defensive, fully stretched in long rallies in which the Czech moved him from corner to corner.
He prolonged the match in the third set with an emotional break of Berdych's service in the seventh game but that signalled the end of his brave resistance.