The Serb won their quarter-final 7-5 6-3 6-1 and faces Andy Murray in the semi-finals.
Nadal had previously lost just one match in 71 at Roland Garros, against Robin Soderling in 2009.
"I lost in 2009 and it was not the end," said the Spaniard. "I lost in 2015 and it's not the end."
He added: "I hope to be back here the next year with another chance."
Nadal, who turned 29 on Wednesday, was seeded sixth in Paris after failing to win a title in the European clay-court season, and that lack of form eventually caught up with him.
"It's not a big surprise, no, after a year that I didn't win enough before here," added Nadal, who has won just one title, in Buenos Aires, since claiming his ninth French Open victory last June.
"It was something that could happen. When you see the draw, quarter-finals against Novak, obviously that is early for a big match like that. I was playing fine.
"I am happy the way that I recovered my level the last month, but probably not enough yet to play against and to win against Novak.
"To play, yes. I competed, but not to win."
Nadal had been bidding to become the first player in the Open era, and only the second ever, to win one of the Grand Slam singles titles 10 times.
"I don't like to talk about dynasty or these kind of things," he said.
"I have been very successful here for nine years out of 11. I lost twice. Everybody loses in every place. I lost not many times here, and that day arrived today.
"Again, I accept it like I always accept the defeats, and there is only one sure thing: I want to work harder even than before to come back stronger."
Nadal will now head into the grass-court season and Wimbledon, where he lost in the fourth round against Australian Nick Kyrgios in 2014.
"Last year I didn't play bad on grass," said the two-time All England Club champion.
"I played a good Wimbledon. I had a good chance to be in quarter-finals. I lost a match that I could win.
"That's it. I am booked for Stuttgart and Queen's and then in Wimbledon probably."