|Isner's big serve and forehand proved too much for Jo-Wilfried Tsonga as he defeated the Frenchman 6-3 7-6 (4) 5-7 6-3 to put the US in the semi-finals [EPA]
Holders Spain set up a heavyweight Davis Cup semi-final clash against the United States when David Ferrer cruised to a 7-5 6-3 6-3 victory over Austria's Juergen Melzer to give the hosts an unassailable 3-1 lead on Sunday.
All four ties were still open on the third day of the World Group quarter-finals and John Isner wrapped up victory for the US when he fought past Jo-Wilfried Tsonga 6-3 7-6 5-7 6-3 to inflict the first French home defeat in six years.
Czech Republic went through on the other side of the draw after Tomas Berdych edged Janko Tipsarevic 7-6 7-6 7-6 in Prague as the home side gained revenge for their last-four defeat to Serbia in 2010.
Their opponents in September's semi-final will be Argentina, who are seeking to go one better than their runner-up finishes to Spain in 2008 and 2011.
Juan Martin Del Potro was far too strong for Marin Cilic in the opening reverse singles in Buenos Aires, the world number 10 crushing the Croat 6-1 6-2 6-1 for a decisive 3-1 lead and sealing victory with an ace.
In a blustery Marina d'Or on the Spanish coast, the tenacious Ferrer was far more consistent than an error-prone Melzer and was rarely under pressure as he secured his second point of the best-of-five tie 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 in an interview with Spanish television after both players struggled with swirling winds and uneven bounce.
"It's great news that we are playing at home in front of our own fans in the semis," Corretja added.
Spain missed a chance to wrap up the tie on Saturday when doubles pair Marcel Granollers and Marc Lopez surrendered a one-set lead and were beaten by Oliver Marach and Alexander Peya.
Undefeated in 23 home ties, they remain favourites to win a fourth title in five years despite the absence of talismanic 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 - who has won all 14 of his Davis Cup singles matches on clay – 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 red dirt in the September 14-16 tie.
Almagro beat Peya 7-5 7-5 to secure a 4-1 success for Spain.
Against the French, the Americans shrugged off the absence of world number nine Mardy Fish and relied on an in-form Isner to lead the charge at the glamorous Monte Carlo Country Club.
The towering 26-year-old, who humbled Gilles Simon on Friday before the Bryan brothers won Saturday's doubles, has been in fine form this year as he has chalked up victories over Roger Federer and world number one Novak Djokovic.
Now ranked number 11, he was instrumental in putting his country through to the semi-finals for the first time since 2008, serving 16 aces against Tsonga and losing his serve to the Frenchman just once.
"I like playing on clay," said Isner, whose four wins in four matches on the surface this year suggest he could be a challenger for titles during the clay season, which moves into top gear at this month's Monte Carlo Masters.
"I played three of my best matches this year, my best wins have come on clay," he added. "It's a surface I enjoy playing on and a surface I feel I can do very well on."
US captain Jim Courier heaped praise on Isner and said he was "shocked" his team were still alive in the competition.
"Spain, we'll probably lose it on paper but we don't play them on paper," the former world number one told a news conference.
"We've got players who are capable, passionate and hungry. We'll definitely be the underdog but we'll be ready."
The 3-2 defeat for France signalled the end of Guy Forget's stint as captain and he was gracious in defeat 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.