Aiming for his fifth title at the Foro Italico in six years, Nadal had trouble finding his range off Wawrinka's powerful serve but finally managed to break the 26th-ranked Swiss player to close out the first set, then cruised from there.
Wawrinka, the 2008 runner-up, dropped only two points in his first four service games.
"The first set was level for a long time. He was holding serve much easier than me. All the games on my serve were harder than his," Nadal said. "But at 5-4 I started to play really well with some good drop shots."
Nadal then began approaching the net in the second set.
"I am going to the net more," he said. "You can go to the net more when you're dominating the points."
Nadal improved his record on clay this season to 8-0, having won the Monte Carlo Masters two weeks ago.
"I played well, but I was definitely playing better in Monte Carlo," Nadal said.
Nadal's only loss at this French Open warmup came against fellow Spaniard Juan Carlos Ferrero in the opening round two years ago, when he was bothered by a foot blister.
Nadal's semifinal opponent will be either Ernests Gulbis or Feliciano Lopez, who were playing the night match.
Earlier, Fernando Verdasco extended his impressive form on clay with a grueling 7-6 (4), 3-6, 6-4 win over Novak Djokovic.
Verdasco has reached the final of his last two events _ losing to Nadal in Monte Carlo and winning last week's Barcelona Open. In the semifinals, Verdasco will face David Ferrer, who cruised past Jo-Wilfried Tsonga 6-4, 6-1.
Roger Federer and Swiss Davis Cup teammate Yves Allegro were eliminated from the doubles tournament by American pair John Isner and Sam Querrey 6-4, 6-4.
Federer lost his opener in singles to Gulbis on Tuesday.
Between Verdasco and Djokovic the first set alone lasted nearly 1 1/2 hours and the sixth-seeded Verdasco closed out the match with an ace down the middle after 3 hours, 18 minutes of long baseline rallies under a glaring sun.
"When you face someone who always makes you play one more shot on every point it's not easy to play a quick match," Djokovic said. "So I knew it was going to be a long match today.
"The match could have gone either way. It was decided by one or two points."
Verdasco also beat Djokovic in the Monte Carlo semifinals, although with a relatively straightforward 6-2, 6-2 score.
The turning point this time didn't come until Verdasco won a marathon game on his sixth break point to take a 2-1 lead in the third set, running down a drop shot from Djokovic and forcing the exhausted Serb to hit into the net.
Djokovic committed 46 unforced errors to Verdasco's 40.
"My backhand wasn't at the level I wanted it to be at today, and I struggled a little with my serve, but I'm happy more or less with the way I played," Djokovic said. "If there was one different thing I could've done I would have liked to play better on the important points."