The Argentine threw in the towel during his first-round encounter with Somdev Devvarman after a lengthy medical timeout at the end of the first set failed to rectify the problem. He was trailing 7-6(3).
Del Potro, a former US Open champion, underwent surgery on his wrist four years ago before making a successful return to the court, winning the ATP Tour's comeback player of the year award in 2011.
But this latest blow - on his other wrist - has left the 25-year-old wondering whether he will require another operation and what that could mean for his career.
"It's not really positive for my future. But I will do whatever the doctor says and I will have to be as strong as ever," he said. "Now I will see what he says for the future, and I will let you know very soon what my plans are going to be.
"I cannot say that [it will be surgery] yet - but I'm feeling similar pains to the other hand and what I felt four years ago. It's not really positive for my future. But I will do whatever the doctor says and I will have to be as strong as ever.
"I don't feel really well. My wrist is hurting a lot, and, you know, everybody knows what's happened to me four years ago with my other wrist.
"It was really tough to play today and I tried everything, but it's very difficult to play in these conditions [windy] you know. I was playing slices and I could not be the player I would like to be.
"It's hurting all the time, sometimes less and sometimes a little more. But it's hurting, and I have been in contact with my doctor all the time. He's trying to keep me motivated to keep playing, but I know what is my limit playing on court. Today was enough."