It is the second year in a row Nadal has been eliminated early at the Grand Slam event. Last year, it was unsung Czech Lukas Rosol who bounced the Spaniard at Wimbledon in the second round.
Darcis defeated the fifth-seeded Nadal 7-6 (7-4), 7-6 (10-8), 6-4, on Court 1 at the All England Club, inflicting his first-ever opening-round loss at a Grand Slam event.
Nadal, 27, who appeared to be dealing with a left leg injury Monday, had been 34-0 when playing the first round of a major. His Wimbledon championships in 2008 and 2010 are among his 12 Grand Slam titles overall, including the French Open this month.
Darcis, 29, whose last ATP World Tour win was in Memphis five years ago, was smooth against the struggling Nadal and punctuated his performance with an impressive match-ending ace.
Federer, ranked and seeded third, cruised past Romanian Victor Hanescu 6-3, 6-2, 6-0 in a 69-minute match, highlighted by seven aces and six breaks. The Swiss star is now 67-7 lifetime at Wimbledon.
"It's a special moment," the seven-time Wimbledon winner said of his return to Centre Court. "It doesn't really change. You feel very unique because you are the one opening the court."
Federer will meet Ukrainian Sergiy Stakhovsky in the second round Wednesday.
In other action, sixth-seeded former Australian Open finalist Jo-Wilfried Tsonga topped Belgian David Goffin 7-6 (7-4), 6-4, 6-3 and 10th-seeded Croat Marin Cilic defeated former Australian Open runner-up and former Wimbledon semifinalist Marcos Baghdatis of Cyprus 6-3, 6-4, 6-4.
Viktor Troicki beat 14th-seeded fellow Serb Janko Tipsarevic 6-3, 6-4, 7-6 (7-5); 18th-seeded American John Isner got past Russian Evgeny Donskoy 6-1, 7-6 (7-5), 7-6 (7-3); and 20th-seeded Russian Mikhail Youzhny ousted Dutchman Robin Haase 6-4, 7-5, 7-5.
In other Day 1 action involving seeds, No. 22 Argentine Juan Monaco bested German Bastian Knittel 6-4, 6-2, 6-3; No. 24 Jerzy Janowicz of Poland eliminated Brit Kyle Edmund 6-2, 6-2, 6-4; No. 25 Benoit Paire of France defeated Romanian Adrian Ungur 6-4, 4-6, 6-3, 6-1; and Austrian Jurgen Melzer knocked off No. 30 Italian Fabio Fognini 6-7 (5-7), 7-5, 6-3, 6-2.