Roddick, who turned 30 on Thursday, delivered the shocking announcement at a news conference ahead of his Friday match against Australian Bernard Tomic inside Arthur Ashe Stadium.
"I just feel like it's time," he said. "I don't know that I'm healthy enough or committed enough to go another year.
"I've always wanted to, in a perfect world, finish at this event. I have a lot of family and friends here. I've thought all year that I would know when I got to this tournament.
"When I was playing my first round, I knew."
Roddick, who beat fellow American Rhyne Williams 6-3 6-4 6-4 in the opening round, is seeded 20th at the US Open, the last of the year's four Grand Slam tournaments.
He said his decision to call it quits after 13 years as a professional, "has been a process, certainly not days".
"Certain parts of the year I've thought about it," Roddick said. "Just with the way my body feels. With the way that I'm able to compete now, I don't know that it's good enough.
"I don't know that I've ever been someone who's interested in existing on tour. I have a lot of other interests and a lot of other things that excite me."
Roddick, who won the 2003 US Open, was a Wimbledon finalist in 2004, 2005 and 2009. He lost to current world number one and 17-times Grand Slam winner Roger Federer each time.
Currently ranked 22nd in the world, Roddick has won 32 singles titles and four doubles titles and pocketed $20,517,390 in career earnings.
Roddick denied that turning 30 was the tipping point.
"A number is a number," he said. "But I think wear and tear and miles is something that's not really an age thing. If you look at my contemporaries that started with me, Roger (Federer) is the only one that's still going and still going strong.
"It's a matter of how I feel. I feel like I'm able to compete at the highest level.
"Frankly, these guys have gotten really, really, really good. I'm not sure that with compromised health that I can do what I want to do right now."
Few would have guessed after Roddick won the US Open in 2003 that he would never win another Major title. But his best chances were always thwarted by Federer, the Wimbledon master.
Roddick said he would rather walk away from the game than give less than 100 per cent effort.
"I was pretty good for a long time," he said. "For 13 or 14 years, I was invested fully, every day. I've seen a lot of people throughout that time be invested for a year, kind of tap out for a year, come back.
"I've been pretty good about keeping my nose to the grindstone. I feel like I won a lot of matches from hard work and persistence."
Wimbledon and Olympic champion Serena Williams said the news came as no surprise.
"I knew for a while," she said. "I've known Andy for so many years, since we were 10 years old. He told me it would probably be his last tournament.
"I was hoping he would change his mind but I guess he didn't. He's been so amazing for American tennis and really exciting to watch and I'm sad to see another face gone."
Roddick owns 33 singles victories in Davis Cup competition, second most all-time in US history, behind John McEnroe's 41.
He married model and actress Brooklyn Decker in 2009 at their home in Austin, Texas.
Roddick said Flushing Meadows is a special place, having given him "the highest of highs and probably the lowest of lows".
He added: "It's certainly never been boring. I've always enjoyed the energy. I feel like each Grand Slam is almost a microcosm of the place it's played in.
"This is a show. It's New York City in every way. I'm glad that I've been a very, very small part of it."