Bob and Mike Bryan's victory in Saturday's doubles rubber had put the visitors 2-1 ahead, and the much-improved Isner finished the job.
Spain can book a place in the final if Marcel Granollers and Marc Lopez can upset world No.1 doubles pair, Bob and Mike Bryan.
Skupski and Fleming reached the second round at Wimbledon before losing to world number two doubles pair Bob and Mike Bryan in three sets, 6-2 6-4 7-6.
The American gold rush at SW19 continued Saturday as brothers Bob and Mike Bryan won their first Olympic title with a 6-4 7-6 victory over French second seeds Jo-Wilfried Tsonga and Michael Llodra in the men's doubles final.
Nestor and Zimonjic, who saved one match point to defeat arch rivals Bob Bryan and Mike Bryan in Saturday's semi-finals, were pushed all the way in the opening set before easing through to triumph in this end-of-season tournament for the second time in three years.
Skupski and his doubles partner Colin Fleming have made great strides over the past 12 months and their form has seen them beat United States brothers and world number one's Mike and Bob Bryan.
The world's top team, Mike and Bob Bryan, who have won their first two matches in London, are fortunate to share not only DNA but also U.S. citizenship.
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"I'm all for bringing more kids into the game and having more tournaments with all kinds of balls and rackets, " said Wayne Bryan, whose sons, Bob and Mike, are the world's top doubles team.
The U.S., who are without Andy Roddick or Mardy Fish, will look to the Bryan brothers (Bob and Mike) to edge them into the lead tomorrow as they face Michael Llodra and Julien Benneteau.
There the U.S. won its fourth straight Davis Cup tie away on clay over France, while the team's formidable doubles pairing of the Bryan brothers, Bob and Mike, returned to the club last week to defend their doubles title.
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