Roddick made the announcement on his 30th birthday, having reached the second round of the final Grand Slam event of the year. He will play a night match Friday against Bernard Tomic knowing a loss will end his career.
"I have decided that this is going to be my last tournament," Roddick said at a news conference held at the USTA National Tennis Center. "I don't know if I'm healthy enough or committed enough to continue another year."
He came into the U.S. Open seeded No. 20 and ranked 22nd in the world.
His only major championship came at the U.S. Open in 2003. He was runner-up in the event in 2006 and reached the finals at Wimbledon three times without winning.
At the end of the 2003 season he was ranked No. 1 in the world at the age of 21 years, 3 months, the youngest American to hold that position.
Injuries have plagued him during his career, one that has seen him win 33 Davis Cup matches.
"I got to play in the Wimbledon finals and be the guy on the Davis Cup team," Roddick said.
He has won 32 tournaments in his 13-year career, two of those titles coming in 2012.
"I wanted an opportunity to say goodbye," Roddick said. "I hope I'm sticking around (past Friday's match)."