"I don't (know) what the problem is yet. It seems like the bone in the foot," the Spaniard said after the nearly four-hour-long contest. "I will get it checked out tomorrow. At one moment at the end of the first set I thought I might have to retire."
The world No. 1 and defending Wimbledon champion will face American Mardy Fish, ranked 10th, in the quarterfinals.
Del Potro, who missed most of last season due to a wrist injury, turned in his finest performance so far at Wimbledon, moving past the second round for the first time.
Nadal has defeated the Argentine five of the eight times they have faced each other.
The last time the Spaniard lost a match on the grass at Wimbledon was 2007, when Switzerland's Roger Federer prevailed in a five-set final.
Nadal won Wimbledon the following year and returned in 2010 to reclaim the title after missing the 2009 tournament.