Fish will face Juan Martin del Potro of Argentina, a 7-6 (6), 6-2 winner over American Amer Delic, and Roddick will meet German left-hander Denis Gremelmayr, who upset No. 5 seed Marat Safin of Russia, 3-6, 6-3, 6-2.
"The second set was probably the best set I've played in the last four months or so," said Roddick, who withdrew from Cincinnati with neck and shoulder pain last week and has been dealing with injuries all summer. "It just clicked in and the ball started doing what I wanted.
"This is probably as optimistic as I've been after match in quite awhile."
Fish, the No. 6 seed in the 28-player field, said he turned down an invitation to the Olympic Games in order to maximize his preparation for the U.S. Open, where he "desperately" wants to do well.
"I felt like I could get some serious matches under my belt, and it's a tournament I felt I could win," Fish said.
He hasn't done anything to make him change his opinion, either, losing just one set in three matches. Against Serra he got early service breaks in both sets and said that if he hadn't been broken in the second game of the second set, it would have been a very easy win.
"That 1-0 game was big, having a break and being up 40-15 and losing that," he said. "I felt like mentally he was almost ready to check out if I had won that game."
The Floridian almost won the other tournament he played in Southern California this year, bowing to Novak Djokovic in the Indian Wells final in March after beating three top 10 players, including No. 1 Roger Federer.
Del Potro had to work perhaps harder than he anticipated, too, against the 137th-ranked Delic, who upset No. 7 seed Carlos Moya in the second round.
"I started out very relaxed," the 19-year-old Argentine said, "and when he broke my serve [in the seventh game of the first set], I started playing much better. After that I played very good."