The Spanish former world number one, who has been complaining of nagging knee pain, beat Argentine David Nalbandian in straight sets 6-2, 6-3 in 78 minutes.
Currently the world number five, Nadal went on the attack from the start, breaking his opponent's service before racing to take the first set.
The 31-year-old Nalbandian, a former world number three who now languishes in 93rd place in the ATP rankings, fought back early in the second set but Nadal came from behind to win the match, sparking wild cheers from the crowd.
The Spaniard pocketed a check of $82,300 for his win and thanked the public for "the great support" he received throughout the tournament.
Nadal was the top seed in this $455,775 tournament, his second comeback event following his long absence.
He competed in the Vina del Mar Open in Chile earlier this month, losing the singles and doubles finals last Sunday.
Considered by many to be the best ever clay-court player, Nadal was back on the court in Chile for the first time since suffering a surprise second-round exit at Wimbledon in June.
Since then he has been sidelined by a torn tendon and inflammation in his left knee, with his return this year further delayed by a stomach virus.
The world number five, who has 11 Grand Slam titles under his belt, also won the Brazil Open in 2005, when it was held in Costa do Sauipe in eastern Bahia state.
Last year, the tournament, Brazil's premier tennis event, was moved to Sao Paulo.
It is part of the Latin American clay court swing, along with the Vina del Mar event and the Mexico Open, in Acapulco, where Nadal plans to compete later this month.
The three low-profile Latin American events are routinely ignored by the world's top three players -- Novak Djokovic, Roger Federer and Andy Murray.
Earlier Sunday, Brazilian Bruno Soares teamed up with Austrian Alexander Peya to win the Sao Paulo doubles final against Czech pair Frantisek Cermak and Slovak Michal Mertinak in three sets 6-7 (5), 6-2, 10-7.