The 21-year-old from Thornhill, Ont., has yet to earn a victory at the picturesque Foro Italico after being eliminated at last year's tournament in the first round on red clay.
Mayer dispatched Raonic in 91 minutes.
"I was playing quite well," said Raonic. "He just played better. He jumped on everything I hit, I couldn’t rise to his level today.
Raonic ended his week in Rome with a modest eight aces. He suffered two breaks on his big serve which had threatened No. 2-ranked Roger Federer earlier this week in the second round of the Madrid Open.
"Today was tough conditions," said Raonic of the hot, dry spring weather in the capital. "I could have done a few things better.
"But I'm gaining experience in these situations. I didn't play my best tennis but I played OK. My goal is to compete with the guys on a regular basis. I'm always trying to improve my game."
Raonic, ranked 23rd, was pipped by a player one spot below him (24th) on the ATP list and one who has now claimed only five wins since January.
"He played well to neutralize my game," said Raonic, who can expect a seeding at the French Open which starts May 27. "He made me feel uncomfortable all the time on court.
"I began well but his game frustrated me, he was always saving himself and it was heavy going."
On the women's side, Alexandra Wozniak of Blainville, Que., earned a place in the WTA draw after beating Italian Natassja Burnett 7-6 (3), 4-6, 6-4 in a match that lasted two hours 38 minutes.