Ferrer recovered from a first-set wobble to score an ultimately comfortable 4-6 6-2 6-2 6-4 win against Querrey on the clay before Almagro dug deep to see off a tiring Isner 6-4 4-6 6-4 3-6 7-5 in the semi-finals.
The towering Isner, who appeared to be suffering from cramp towards the end of a thrilling match, several times needed his powerful serve to stay in contention and saved three match points earlier in the deciding set before capitulating.
Almagro collapsed to the ground when an Isner forehand flew long on the fourth match point before climbing to his feet and kissing his racquet as the raucous crowd celebrated around the purpose-built outdoor arena in the northern Spanish city.
It was 12th-ranked Almagro's second win in two matches against number 10 Isner following his four-set victory on the grass at Wimbledon last year.
World number five Ferrer only had a few days to prepare for the best-of-five tie following his run to the semi-finals of the US Open but he ultimately proved too strong on his favoured surface against the 26th-ranked Querrey.
Ferrer is leading the Spanish bid for a place in November's final in the absence of the injured Rafa Nadal and his victory was his 15th in 15 Davis Cup singles rubbers on clay and his 20th in 24 matches overall.
"It was a very tough match. He didn't make it easy for me," Ferrer told Spanish television.
"I managed to stay focused mentally and the important thing is the victory."
Top-ranked American pair Bob and Mike Bryan are firm favourites to take Saturday's doubles point when they meet Marcel Granollers and Marc Lopez, with the two reverse singles to come on Sunday.
Spain are bidding for a fourth Davis Cup crown in five years while the US, without the recently-retired Andy Roddick, have not won the competition since 2007.
The winners meet Argentina, who lost to Spain in last year's final, or Czech Republic.
Juan Martin Del Potro gave Argentina a 1-0 lead in Buenos Aires when he thumped Radek Stepanek 6-4 6-4 6-2 on Friday.