Mayer broke Ferrero twice in the second set and saved all five break points he faced to win the match in nearly two hours at the Ibirapuera sporting complex.
The 24-year-old Mayer, ranked 80th in the world, also took advantage of 11 aces, including eight in the first set.
"That first set was key, especially after I had the advantage in the tiebreaker," said Ferrero, who won the Brazil Open in 2010. "But Mayer had a great match throughout and served really well."
The 43rd-ranked Ferrero, No. 1 in the world in 2003 after winning the French Open, has won only one match this season.
"My confidence took a hit after the 1-6 in the second set but I kept focused and was able to revert the score in the third," said the 38th-ranked Bellucci, Brazil's top-ranked player.
Earlier Wednesday, eighth-seeded Albert Ramos of Spain ousted Santiago Giraldo of Colombia 6-3, 6-4, capitalizing on his two break opportunities in the second set to beat the Colombian for the first time in three matches.
South America's biggest city is hosting the clay-court event for the first time after 11 editions in the northeastern city of Costa do Sauipe.