The American duo took their Laver Cup record as a pairing to 3-0 as they came through 5-7 6-4 10-8 in Geneva, collecting three priceless points for the red team.
Having trailed 7-3 at one stage on Day 2, Team World moves 8-7 ahead with three matches to follow – and a target of 13 points to take the trophy for the first time.
“It feels great, the energy’s amazing and we’ve got a lead,” said Team World Captain John McEnroe.
It was the Tsitsipas serve that faltered first, a Sock return winner setting up two break points before a loose Federer volley gave World a 2-1 lead.
The lead lasted just one game, however, as Isner’s serve was broken to level things up and it looked to be heading for a tiebreaker until Europe made the decisive breakthrough in game 12.
An instinctive reactive volley from Isner early in the second set changed the momentum, a lone break enough to give World the second set, albeit after a dramatic final game that saw Europe miss chances to break back.
As ever, the match tiebreaker was a gripping, rollercoaster affair, with World making the key move with four straight points to go 7-4 clear.
Federer saved the first match point with a volley, but Tsitsipas could not control a big Isner serve on the second and Team World could celebrate another doubles success.