Nadal, fresh from a record-breaking seventh French Open win, enjoyed a 7-6 (7/0), 6-2, 6-3 victory over Brazil's Thomaz Bellucci despite having trailed 4-0 in the first set.
"It's always tough to make the change from clay to grass, especially when over the last couple of months I played almost every match on tour. Physically you start having some troubles," admitted Nadal, the 2008 and 2010 champion.
"I'm very happy to be back on probably the best court in the world and winning in three sets is good for me." Serena Williams, the 2002, 2003, 2009 and 2010 champion, reached the second round with a 6-2, 6-4 win over Barbora Zahlavova Strycova of the Czech Republic. The American sixth seed triumphed on the same Court Two where sister Venus had on Monday suffered her first opening round loss at Wimbledon since 1997.
"It always has some sort of an effect," said Serena of her sister's loss. "I always want to play even better if she's out of the tournament."
Defending champion Petra Kvitova overcame early nerves to progress 6-4, 6-4 against Akgul Amanmuradova of Uzbekistan, but the 22-year-old did it the hard way, having trailed 3-0 and 4-1 in the first set.
World number two Victoria Azarenka eased through, seeing off America's Irina Falconi 6-1, 6-4. Lleyton Hewitt's 10th anniversary party of his 2002 title was gatecrashed by French fifth seed Jo-Wilfried Tsonga who cruised to a 6-3, 6-4, 6-4 win, handing the Australian his earliest exit at the All England Club since 2003.
His loss also meant that there will be no Australian man in the second round for the first time since 1938 after compatriots Bernard Tomic, a quarter-finalist last year, Matthew Ebdon and Marinko Matosevic were also beaten.
The injury-plagued Hewitt, 31, playing in his 14th Wimbledon but needing a wildcard to do so after his ranking plummeted to 202, underwent radical surgery to cut bone out of his big toe in February.
But he refused to entertain any notion that the problems of Australian tennis mirrored a decline in the country's sporting prowess in general.
"I reckon we'll go alright at the Olympics," he said.
American hopes, which were so badly bruised by the opening day exits of five-time champion Venus and big-serving John Isner, were earlier boosted by Mardy Fish and Bryan Baker.
Fish made a winning return to tennis in his first match following surgery to address a frightening heart scare.
The world number 12 beat Spain's Ruben Ramirez-Hidalgo 7-6 (7/3), 7-5 7-6 (7/1), but later pulled out of a mandatory press conference after complaining of feeling unwell.
Baker, who lost six years of his career to an assortment of injuries and underwent five operations, clinched a first ever win at Wimbledon, beating Portugal's Rui Machado 7-6 (7/2), 6-4, 6-0. The 27-year-old reached the second round of the French Open last month in what was his first Grand Slam appearance since the 2005 US Open.
And his good run continued at the All England Club where he came through three rounds of qualifying to make the main draw.
"I'd be lying if I sat here and said that I expected all this to happen right now when I was going through all those surgeries," said Baker.
"But I never gave up the hope that I would be able to come back."