Nadal sealed his fifth victory in seven tournaments since returning from a seven-month injury layoff in February.
The Spaniard, who now holds a 9-0 career record over the Swiss, rolled through the first set thanks to two early breaks in little over half an hour.
And after a little more resistance from Wawrinka in the second, Nadal broke again to go ahead 4-3 before serving out to claim his 23rd Masters Series title.
Wawrinka, who will return to the world's top 10 next week for the first time in five years, went into Sunday's final on a nine-match winning streak, having won his seventh ATP title last week at the Portugal Open.
The Swiss beat sixth seed Tomas Berdych 6-3, 4-6, 6-4 in a semifinal on Saturday.
The Lausanne native was contesting his second Masters final, after finishing runner-up to Novak Djokovic in the 2008 Rome Masters.
Berdych, who knocked out world number three Andy Murray in the quarterfinals, was bidding to reach the Madrid final for the second year in a row, having finished runner-up last year to Roger Federer.
The world number one and two players – Djokovic and Federer – were both beaten early at the Madrid Masters.