The US Open semi-finalist was jolted by Sam Querrey at the outset of the tie, when the American took the opening set against all expectations on the red clay.
Ferrer is among the world's very best on the surface, and the world number five soon began to show his pedigree, cutting down on the error count which had been uncharacteristically high early on.
Once the 30-year-old levelled the contest, it seemed inevitable Querrey would bow to Ferrer in four sets. Despite having as many as nine break points in the fourth set, Querrey failed to convert.
In three minutes over three hours, Ferrer finished up a 4-6 6-2 6-2 6-4 winner over a man still battling back to where he wants to be in the world rankings after an injury-ruined 2011 season.
One-time world number 17 Querrey is knocking on the door of the top 20 again but a lack of clay-court expertise was his undoing.
Reigning Davis Cup champions Spain are hot favourites to win the tie and move through to a final against Argentina or the Czech Republic, who were getting their match under way in Buenos Aires.
Even without team talisman Rafael Nadal, who could miss the rest of the season with injury, Spain appeared to have a considerable edge over Jim Courier's US team.
Last year Spain saw off the United States in a quarter-final staged on hard courts in Houston.
Juan Martin del Potro put Argentina 1-0 ahead against the Czech Republic with a convincing win over Radek Stepanek, the 2009 US Open champion prevailing 6-4 6-4 6-2.
In Gijon, the United States were threatening to level the tie against Spain.
Almagro, leading by two sets to one, had six break points against the Isner serve early in the fourth set but could not capitalise.
And they went to a decider when Isner broke Almagro in the eighth game and held easily.