The first-set decider tied the record of the longest ever played by the Spaniard, who went the same distance in 2009 but lost 14-12 to Richard Gasquet.
The unseeded Wawrinka had five set point chances of his own which he could not convert. Nadal took the first set on his fourth chance.
Nadal is playing in his first ATP event since winning a second Wimbledon title and then watching Spain win the FIFA World Cup in South Africa.
He also had physical therapy on his knee, a constant cause of worry in his career.
Nadal will line up Thursday against South African qualifier Kevin Anderson, who knocked out American Sam Querrey 7-6 (7/4), 4-6, 6-4.
Second-seeded Novak Djokovic struggled to close out his opening win in searing heat while title holder Andy Murray played it cool as he rallied for a victory over Xavier Malisse.
Djokovic required multiple match points to down Frenchman Julien Benneteau 7-5, 7-5. Murray broke Malisse twice to end the first set and easily powered through to A 7-5, 6-2 victory.
Murray slowly seized control, firing seven aces and breaking his 30-year-old opponent. For Djokovic, however, it was a struggle to the end. The Serb admitted that his longstanding discomfort in hot weather again came into play.
Djokovic, winner of the 2007 Canadian title, smashed a racket in the second set before finally improving to 4-1 in his career series against Benneteau.
He was playing for the first time since leading his country into the Davis Cup semi-finals last month.
Three Frenchman won through, two through upsets.
Jeremy Chardy put out Spanish ninth seed Fernando Verdasco 6-7 (7/9), 7-6 (7/5), 6-2 while Michael Llodra did the same to another Iberian, number 14 Nicolas Almagro 7-6 (7/5), 6-2. The 15th seed Gael Monfils beat Dutchman Thiemo de Bakker 7-5, 6-3 to set up a match with Murray.
Russia’s world number six Nikolay Davydenko beat Italian Fabio Fognini 7-5, 6-1 but Ukranian Alexandr Dolgopolov upset 12th seed Russian Mikhail Youzhny 1-6, 7-6 (7/4), 7-5.
Last week’s Washington winner David Nalbandian continued his comeback success from hip surgery and other injuries, putting out Spain’s Tommy Robredo 6-3, 6-0.