Darcis, 29, won the match in straight sets, 7-6, 7-6, 6-4, against the fifth-seeded Nadal. He ended the third set with an ace.
Darcis is currently ranked No. 690 worldwide, and hit his career high at No. 44 in 2008. He was unseeded going into Wimbledon.
The loss comes just after Nadal said he should not have played at Wimbledon last year, after a second-round defeat to then world No. 100 Lukas Rosol. He pulled out of defending his Olympic title one month later, citing a nagging knee injury.
Nadal was out seven months from there, but returned in February to win his eighth French Open title. He had won 43 of his 45 matches since his comeback.
That same knee issue plagued his play against Darcis in the first round. Nadal won Wimbledon in 2008 and 2010.
This changes the pace for Federer, who had expected to face Nadal in the quarterfinals.