The world No. 17 Isner stunned Federer in 4-6, 6-3, 7-6 (7-4), 6-2 fashion on red clay, a preferred surface for Federer and certainly the least-favorite surface for the 6-foot-9 Isner, prior to Friday.
The match came to a stunning conclusion when Isner ripped a backhand return winner after 2 hours, 40 minutes of tennis. The players combined for 27 aces, including 14 for the winner from North Carolina.
Federer seemed to cruise in the opening set, as he was never in any kind of danger. But Isner would turn things around in the second, as he broke for a 4-2 advantage on his way to leveling the rubber.
The tight third set went to a tiebreak, which the American won rather easily to stun Swiss onlookers.
Isner then put the petal to the metal in the fourth set, as he broke a lethargic Federer for a 4-2 lead, then consolidated the break with a hold, and closed out the match with his third break of the night to send the sublime Swiss off the court a confused loser.
The 26-year-old Isner wound up with 19 more winners (85-66) than the iconic Federer on Day 1.
This marks the 16-time Grand Slam champion Federer's first World Group action since 2004, as he had played in only a few playoffs and zonal matchups since then.
The 30-year-old Swiss is now 30-7 in his Davis Cup singles, while Isner improved to 2-3.
The world No. 8 Fish, playing on his worst surface, came from behind to best the 28th-ranked Wawrinka 6-2, 4-6, 4-6, 6-1, 9-7 on the dirt at Forum Fribourg. The grueling rubber finally ended after 4 hours, 26 minutes when Fish converted on his third match point, a cross-court volley winner.
Fish, who improved to 7-7 in his career Davis Cup singles, wound up with 15 aces and broke Wawrinka's serve seven times, compared to four breaks for the Swiss loser.
Saturday's doubles in Fribourg tentatively pit an American tandem of Mike Bryan and Ryan Harrison against a Swiss pairing of Federer and Wawrinka, who were the gold medal winners at the Olympic Summer Games in Beijing in 2008. Bob Bryan made himself unavailable to play doubles for the U.S. this week after his wife gave birth to their first child last week.
Sunday's reverse singles currently call for the former world No. 1 and currently third-ranked Federer to battle Fish and Wawrinka to encounter Isner.
The 32-time Davis Cup champion Americans are playing here without injured star Andy Roddick.
The U.S. is 2-1 all-time versus Switzerland, including a victory in the final back in 1992. The Swiss, however, are 1-0 all-time against the Americans on home soil, with the victory coming 11 years ago in Basel.
Team USA is captained former world No. 1 star Jim Courier, while Switzerland, which has never captured the Davis Cup, is led by Severin Luthi.
The USA-Switzerland winner will meet the Canada-France victor in the quarterfinals in April.