The world number two came from a set down to defeat big-serving American Isner 6-7 (5/7), 7-6 (8/6), 10/7 in an enthralling battle at Chicago's United Center.
Federer's win left Europe 10-8 ahead with two more singles rubbers left to play.
One victory would be enough to see Europe retain the crown they won at the inaugural event in Prague last year.
The win was testimony to Federer's remarkable physical conditioning.
The 37-year-old Swiss outlasted Isner less than an hour after he had been beaten in the day's opening doubles game.
Federer and Germany's Alexander Zverev had slipped to a 4-6, 7-6 (7/2), 11/9 loss to Isner and partner Jack Sock.
Isner and Sock saved two match points in the super tiebreaker on their way to their doubles win.
Federer and Zverev looked set to give Europe a commanding 10-5 lead in the match after taking two match points in the super tiebreaker at the United Center.
In later games, Zverev will face South Africa's Kevin Anderson before Novak Djokovic takes on Nick Kyrgios in the final rubber of the three-day tournament.