Isner overcame Mahut in 90 minutes to give the U.S. an insurmountable 2-0 lead over France in the team competition. The match lasted 9 1/2 hours and 161 games less than their previous record-breaking encounter.
The Wimbledon match, the longest-ever in professional tennis history, stretched over three days and finished at 70-68 in the fifth set.
A repeat was never likely in any event but the 19th-ranked Isner started the stronger in Perth, breaking Mahut immediately, and held firm to take the first set 6-3.
Mahut, who is only in the French team after replacing the injured Gael Monfils, bounced back in the second, hitting just four unforced errors to the American's 20, but could not make any inroads into Isner's serve. Neck and neck in the second set tiebreak, it was Isner who converted the opportunity.
"Had I lost that second set it might have gone four hours so I was lucky to finish it in two," Isner said. "For the first match of the year I was pretty pleased with how I played.
"I got on top of him early in the first set, he picked up his game in the second, but I stayed the course with mine. I didn't get to break, but fortunately for me I came up with my best serves. It's always an honor to share the court with him."
Isner later teamed up with Bethanie Mattek-Sands to secure a 3-0 victory for the United States, beating Mahut and Kristina Mladenovic 2-6, 6-3, 10-8 in the mixed doubles.
Mattek-Sands had earlier given the Americans a 1-0 lead by defeating former top-ranked junior Mladenovic 3-6, 6-3, 6-1.
The 56th-ranked American, dressed in black knee-high socks and basketball shoes, recovered from dropping the opening set against an opponent ranked 301st, and secured an early break in the second set. Although Mladenovic took the break back, Mattek-Sands continued to disrupt her rhythm, and secured the set.
The third set, in which Mladenovic received treatment for a knee injury, was one-way traffic in favor of the American, who replaced the injured Serena Williams.
"She's a great player," Mattek-Sands said of Mladenovic. "I've never played her before. It's tough going out there and not playing someone that you're used to seeing across the net. So I had to go out there and make my own game plan as I went."
"She came out crushing the ball. She wasn't afraid to come in and take balls on the rise, which is normally my game. Toward the end of the second set and the third, I switched that around and started coming in more."
Mattek-Sands and Isner are due to complete the tie with the mixed doubles against Mladenovic and Mahut.
The U.S. and France are in Group B along with Britain and Italy.
In the day's earlier matchup, Potito Starace and Francesca Schiavone beat Andy Murray and Laura Robson in the deciding mixed doubles match 6-7 (1), 7-6 (6), 7-6 (2) to give Italy a 2-1 win over Britain.
Schiavone beat the 16-year-old Robson 7-5, 6-3 in women's singles to give Italy the early lead before Murray opened his 2011 season strong with a 7-5, 6-1 win over Starace.
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