Federer played his first match since the U.S. Open, where he lost to Novak Djokovic in the semifinals. He showed few signs of rustiness as he moved into the third round, joining top-ranked Rafael Nadal, Andy Murray and Djokovic.
The third-ranked Swiss broke Isner's big serve twice, but the highlight of his win came in the second set when he chased down a lob and flicked the ball back through his legs. Isner was so surprised, he put his volley into the net.
Federer has successfully pulled off the shot -- also known as a "tweener" -- at the previous two U.S. Opens as well as at the Dubai Open in 2007.
"I'm hitting that shot so well now, it's almost the most consistent shot in tennis these days," Federer said, joking.
Top-ranked Nadal, fresh from winning the Japan Open on Sunday, began his quest for an eighth title of the season with a 6-4, 6-4 win over Stanislas Wawrinka. Murray beat 465th-ranked Chinese wild card Bai Yan 6-2, 6-2. Djokovic defeated Ivan Ljubicic 6-3, 6-3, just two days after winning the China Open in Beijing.
Wawrinka hit 32 winners to Nadal's 17 and eight aces to Nadal's two -- but also finished with 36 unforced errors.
"Wawrinka is a very good player and it's very difficult to have a victory today in straight sets," Nadal said. "I'm happy for that. For sure it wasn't easy, but it wasn't one of these very, very difficult days."
Roddick slipped while trying to change directions during his match against Garcia-Lopez. The 11th-ranked American had his right thigh taped and played only one more game before quitting. He said he aggravated his groin muscle in his quarterfinal match at the Japan Open last week and it hadn't fully healed.
"It was to the point where moving at all felt like I was getting stabbed in the leg," Roddick said. "It's just frustrating. You've got to be able to get a little bit of momentum going, and I just feel like I haven't been able to do that since April or May and a lot of that has been out of my hands."
Roddick is attempting to finish in the top 10 for the ninth straight season.
Defending champion Nikolay Davydenko lost to Mischa Zverev 6-4, 7-6 (3). Davydenko dropped six straight points in the second-set tiebreak and then saved three match points before Zverev clinched it with a forehand winner down the line.
Djokovic was playing doubles later Wednesday to prepare for Serbia's Davis Cup final against France in December. He said he wasn't worried the extra matches would tire him out.
"I'm playing well, moving well, motivated mentally and full of energy. I'm hoping that it's going to stay that way," Djokovic said. "I didn't spend that much energy in Beijing. I won without dropping a set the whole tournament."