Napoles, nicknamed Mantequilla (Butter), debuted as a professional boxer on August 2, 1958 in Cuba, knocking out Julio Rojas in the first round. Napoles' first 18 bouts were in Cuba, against mostly unknown competition. He did beat Angel Garcia and Leslie Grant, and lost to Hilton Smith (who handled Napoles his first defeat), however.
It was at this point of his career that Napoles moved to Mexico. After beating Enrique Carabeo in March of 1961, Napoles found himself a new, outside the ring challenge: Cuban president Fidel Castro banned professional boxing in Cuba, and Napoles soon found his career in jeopardy.
He found asylum in Mexico, where he soon found himself back inside the ring, beating Enrique Camarena by a knockout in two on July 21 of 1962. He won all four of his fights that year.
In 1963, he won seven bouts and lost two. He was defeated by Tony Perez and Alfredo Urbina, both by decision, but he beat JC Morgan, by knockout in seven, in Venezuela.
1964 was a fabulous year for Napoles. He travelled to Japan, where he beat Taketeru Yoshimoto by knockout in round one, and he beat future world champion Carlos Hernandez by knockout in seven. this time back in Venezuela. In addition to those wins, he avenged his loss to Urbina by knocking him out twice, the first time in the first round and the second time in the third.
He won three more fights in 1965, including another win against Morgan, before seeing a raise in opposition quality when he faced the former world Jr. Welterweight champion Eddie Perkins, beating him by decision in ten rounds. For his next fight, he met his own future world title challenger, Adolph Pruitt, beating him by knockout in round three.
In 1966, he won five fights, all by knockout, and lost one, to arch-rival Morgan, who knocked him out in round four. This would be his last loss in four years.
Napoles began a streak of 20 wins in a row, 13 of them before challenging for the world's Welterweight title. These included avenging the loss to Morgan with a two round knockout. During this period, Napoles also became a fan favorite in southern California, and, after beating Fate Davis, on February 15 of 1969 in Mexico, he was given an opportunity to win the world championship when he faced world champion Curtis Cokes in Inglewood, on April 18. Napoles beat Cokes by a knockout in round 13 to become world Welterweight champion, and, as was becoming common place for him, he wore a Mexican hat after the fight. On June 29, he retained the title in a rematch with Cokes by a knockout in round 10 at Mexico City, and on October 12, he outpointed former world champion Emile Griffith in 15, also retaining the title.
Napoles began the decade of the 1970s, by defeating challenger Ernie Lopez by a knockout in round 15 in front of an audience that included former world champion Sugar Ray Robinson on St. Valentine's day, 1970. But after winning two non title bouts, he suffered an upset when he was knocked out in four rounds by Carmen Basilio's nephew Billy Backus, who took the world's Welterweight title from Napoles on December 3 at Syracuse.
After winning one more fight, he and Backus fought again, for the world Welterweight title now in Backus' hands. This time, it was held in Los Angeles, and Napoles recovered the world championship the same way he had lost it: by knockout in round four. After three non-title wins, including one over Jean Josselin, he faced Hedgemon Lewis on December 14, retaining the world title with a decision in 15 rounds.
In 1972, he retained the title knocking out Ralph Charles in seven in England, and then, Pruitt resurfaced again, this time with the world Welterweight title on the line. Napoles retained his crown by knockout in round two.
World traveller Napoles began 1973 by retaining the title against Lopez again, by knockout in seven, then he visited Grenoble, France, where he retained the crown with a 15 round decision over Roger Menetrey, and Toronto, where he beat Clyde Gray, once again retaining the world title with a 15 round decision.
After this, many boxing fans were asking for a fight between Napoles and world Middleweight champion Carlos Monzon. The fight was made possible when Napoles moved in weight to challenge Monzon for Monzon's title, so the two dueled on February 9 of 1974 at a parking lot in Paris. This would be Napoles' only bout at the Middleweight division, as he was defeated by Monzon with a knockout in round seven. Napoles then went back to the Welterweight division, and retained the title twice before the year ended, with a knockout in nine over Lewis, and with a knockout in three over Horacio Saldano.
In 1975, Napoles had two wins over Armando Muniz, both times to retain his world title. The first time, a technical decision win in 12 rounds at Acapulco was a controversial win, so a return match was fought in Los Angeles, where Napoles prevailed by decision.
On December 6 of that year, however, Napoles lost his title to British boxing teacher John H. Stracey, who won over Napoles by a knockout in round six at Mexico City despite being floored by Napoles in round one. After this fight, Napoles announced his retirement. Remarkably, he was able to stay away from the temptation of a comeback, much like Marvin Hagler.
In 1985, Napoles was inducted into the old, Ring Magazine boxing hall of fame, which had its offices at the Madison Square Garden.
In 1990, Napoles was inducted as an member of the original group of members of the modern, International Boxing Hall of Fame in Canastota.
He had a record of 77 wins and 7 losses, with 54 wins by knockout, which makes him a member of the exclusive group of boxers that won 50 or more fights by knockout in their careers.