The tenacious Ferrer was far more consistent than an error-prone Melzer in blustery Marina d'Or and was rarely under pressure as he secured his second point of the best-of-five quarter-final after thrashing Andreas Haider-Maurer on Friday.
"It was quite an uncomfortable match but David was very focused and very disciplined," Spain captain Alex Corretja said after both players struggled with swirling gusts of wind and uneven bounce.
"It's great news that we are playing at home in front of our own fans in the semis," Corretja added.
The towering American, who humbled Gilles Simon in their singles on Friday before the Bryan brothers won Saturday's doubles, has been on fine form this year and was instrumental in putting his country through to the semi-finals for the first time since 2008.
"I gave everything I could in the battle," Tsonga said. "I didn't have much luck today and John took his chances."
Defeat for France signalled the end of Guy Forget's stint as captain and he was gracious in defeat at the glamorous Monte Carlo Country Club in Roquebrune.
"You have to congratulate him, John Isner was huge today," said Forget, who won the Davis Cup as a player with France in 1991 and 1996.
"He played very well and he has a lot of talent," Forget added. "(US captain) Jim Courier is a great leader and he has a lot of class."
Spain, unbeaten in 23 home ties, remain favourites to win a fourth title in five years despite the absence of talisman and world number two Rafa Nadal.
The French Open champion has opted out of the competition this year citing the packed calendar in an Olympic year and is also nursing a knee injury aggravated in Miami last week.
However, with world number five Ferrer in the side and 12th-ranked Nicolas Almagro playing some of the best tennis of his career the US face a tough task to beat the Spanish at home on their favoured clay.
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