Nadal recovered from an early break in the third set after a 50-minute rain delay.
“My first victory here in 2005 is one of my greatest memories,” Nadal said during the trophy presentation. “To have this cup with me so many years later is really specialissimo.”
The victory means Nadal will reclaim the No 1 ranking from Roger Federer today.
Federer is sitting out the clay season to prepare for Wimbledon.
Nadal and Zverev had each won two titles on clay this season entering the final, with Nadal lifting trophies in Monte Carlo and Barcelona and Zverev taking Munich and Madrid.
Nadal improved to 5-0 in his career tally against Zverev and gained an extra measure of confidence entering the French Open, which starts next Sunday.
After two lopsided sets in the men’s final, it began to rain at the start of the third and both players grew upset when fans got up from their seats during and between points.
After firstly a brief delay, the tarps were brought out during a 50-minute stop with Zverev about to serve at 3-2.
Once play resumed, Nadal won four straight games while Zverev, who was on a 13-match winning streak, appeared fatigued.
The Spaniard even showed off his shot-making skills with an over-the-shoulder put away with his back to the net, earning long applause from crowd.
“Congratulations Rafa. Obviously you’re an amazing champion and you proved it again tonight,” Zverev said. “You’re the greatest clay-court player of all time.”
Nadal, who hadn’t won the Italian Open since 2013, picked up a winner’s cheque of €935,000 (£817,000).
Earlier, Elina Svitolina defended the women’s title, facing little resistance from top-ranked Simona Halep in a 6-0, 6-4 win. “I dominated all the match,” Svitolina said.
Just like in last year’s final, Halep appeared bothered by an injury.
Halep called a trainer on to the court for an apparent back problem while trailing 2-3 in the second set ,then exited the court for treatment under a medical timeout.
“I was a little bit too stiff with my body and I couldn’t stay in the rallies,” Halep said. “The muscles were stiff. I couldn’t run.”
Last year, Halep rolled her ankle in the final and lost a set lead to Svitolina.
This time, Svitolina didn’t face a single break point in a match that lasted only 67 minutes. “It’s amazing that I could come and defend my title here,” Svitolina said.
“It’s really something very, very special for me.”
Halep said her physical problems were the result of a long three-set win over Maria Sharapova in the semi-finals a day earlier
“Every time I play against Sharapova the ball is coming very flat and I bend down a lot,” Halep said.
The fourth-ranked Svitolina became the first woman to defend her title at the Foro Italico since Serena Williams accomplished the feat in 2013 and 2014. The Ukrainian picked up a winner’s cheque of €507,000(£443,000) for her 12th career title.
Svitolina improved to 4-2 in her career against Halep, who had already secured the No 1 ranking for another week by reaching the semi-finals.
“She deserved to win for sure,” Halep said. “She didn’t miss. I missed.”
Svitolina, who has never made it beyond the quarter-finals at a major, was hesitant to predict anything for Paris.
“In a Grand Slam it’s very tricky,” she said. “But I’m definitely going to Roland Garros on a high note.”