Aiming for his fifth title at Foro Italico in six years, Nadal had trouble finding his range off Wawrinka's powerful serve. But he finally managed to break the 26th-ranked Swiss player to close the first set before cruising from there.
Nadal improved his record on clay this year 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 warm-up came against fellow Spaniard Juan Carlos Ferrero in the opening round two years ago, when he was bothered by a foot blister.
Fernando Verdasco made another strong showing on clay with a 7-6 (4), 3-6, 6-4 win over Novak Djokovic. The match, featuring long baseline rallies, was played under a glaring sun and lasted 3 hours, 18 minutes. 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.
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."
Verdasco has reached the final of his last two events -- losing to Nadal in Monte Carlo and winning last week's Barcelona Open. The first set of the Verdasco-Djokovic match went nearly 1½ hours. Verdasco, seeded sixth, closed the match with an ace down the middle.
"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."
Verdasco also beat Djokovic in the Monte Carlo semifinals, winning 6-2, 6-2. The turning point this time didn't come until Verdasco won a marathon game on his sixth break point to lead 2-1 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."