Joy was etched all over the Argentine's face when he put away a forehand winner to finally eclipse his plucky opponent 5-7 6-4 6-2 6-7(5) 6-2 in an absorbing match.
"After four hours of playing great tennis, for both sides we closed the battle in a very good way," Del Potro told reporters, having bowed before Nishioka at the net after the contest.
"It was a tough match for sure. Long rallies, long points. We made a great match. I played a little bit better than him and that was the key to the match."
The eighth-seeded Del Potro has twice reached the semi-finals at Roland Garros, including last year, and had plenty of support in overcast conditions on Court Simonne-Mathieu.
However, he found it hard to get going in a first set that saw both players struggle on serve before the 72nd-ranked Nishioka edged ahead and held to open his account.
The 2009 U.S. Open champion Del Potro, more at home on hard courts than clay, settled down in the second though and levelled the match with a forehand winner courtesy of a net cord.
The 30-year-old matched his two breaks in that set with two more in the third to get on top in the match, but Nishioka, 23, won the fourth set tiebreak on his second set point.
That setback sparked Del Potro into action and, having beaten his opponent in their only other meeting, at Delray Beach in February, he was not about to let this one slide.
The world number nine raced into a 5-2 lead and, although clouds enveloped the court, the outlook was bright for Del Potro as he wrapped up the win before punching the air in delight.
Del Potro, who has suffered his fair share of injuries over the years, seemed to be struggling with a slight knee problem and said he had played with some pain but was OK.
"I lost my balance at the beginning of the match and felt pain in my hip and knee also. It's not easy to deal with this kind of pain after all my injuries."
He now faces Australian Jordan Thompson, who beat 40-year-old Ivo Karlovic -- the oldest man to win a match at the French Open since 1973 when he reached the second round on Wednesday.
(Reporting by Ken Ferris; Editing by Hugh Lawson and Toby Davis)
