Vazquez was not convinced that he wanted to be a professional boxer, but he turned professional on January 29, 1981, losing a decision to the future Puerto Rican bantamweight champion William Ramos by a decision in four. His first win came one month later, when he knocked out Felix Cortez in round two on February 26. After one more knockout win, he drew with Eusebio Espinal, future world title challenger of Jiro Watanabe, in six rounds. Two more wins followed before he suffered a serious blow in life: On August 21, the night of Wilfredo Gomez's loss at the hands of Salvador Sanchez, his father suffered a heart attack, dying from it. Vazquez then found the determination to keep on going on as a professional fighter.
Eight days after his father's death, on August 29, Vazquez beat fringe contender Pedro Alindato by a knockout in six. In 1982, he continued on the winning ways, winning all six of his bouts, three by knockout, including two wins over Rudy Perez, by decision in six an by knockout in two. He was supposed to participate at the undercard of the Carnival of Champions in New Orleans, where Gomez beat Lupe Pintor and Thomas Hearns beat Wilfredo Benitez, but an injury during training prevented him from doing so.
In 1983 he won his five bouts, including one over Robert Mullins, by a knockout in three. Then, in 1984, he beat Juan Chiqui Torres by a knockout in four, as part of the undercard of the fight where Gomez beat Juan Laporte, for the Puerto Rican bantamweight title. His next fight, against Julio Guerrero was a no contest, but he closed the year by beating Javier Barajas and Norgie Castro.
Vazquez won two fights in 1985, both by knockout, and then he began 1986 with his first world title try: On February 8, at Miami, Vazquez rose off the canvas in round two and dropped defending WBC world Bantamweight champion Miguel Happy Lora in round four, but eventually, Lora won a 12 round decision.
In May of that year,he had fights against quality opponents within a week of each other; On the 24th, he beat former Gomez world title challenger Jose Cervantes by a knockout in three, but on the 31st, he lost to former world Flyweight champion Antonio Avelar by a knockout also, in round eight.
In 1987, however, he won two fights, including one over Juan Carazo, by knockout in one, before receiving his second world title try, this time for the WBA's world Bantamweight championship. On October 4 of 1987, he became world champion by knocking out Chan-Young Park in 10 rounds at Thailand. He defended his crown with a draw against Tayuka Muruguma, then lost it to Kaokor Galaxi by a decision in twelve. His last fight of 1988 was a 10 round decision loss to Raul Jibaro Perez, future world champion, in Los Angeles. It should be said that Vazquez did not fight in Puerto Rico from 1985 to 1995.
He won two fights in a row and then lost to Venezuela's Israel Contreras by a knockout in round one at Spain. Vazquez felt like he had hit the bottom after that loss, but he refused to give up on boxing, so he came back and won three fights in a row, until he was given an opportunity to challenge Perez in a rematch, for the WBA's world Jr. Featherweight title. On March 28, 1992, Vazquez avenged his earlier loss and became a two division world champion by knocking Perez out in three rounds in Mexico City.
Vazquez was a busy champion his second time around as ruler, beating Freddie Cruz, former world champion Thierry Jacob (twice, by knockout in eight and by knockout in ten}, former world champion Luis Mendoza, Hiroaki Yokota, Yuichi Kasay (by knockout in round one), Yae-Won Choi, former world champion Juan Polo Perez, and IBF world Bantamweight champion Orlando Canizales, the latter by decision during an HBO Boxing telecast.
In his next fight, his first in ten years in Puerto Rico, he lost the title, to Antonio Cermeno, by a decision in twelve.
Two more wins, and then he finished 1995 by conquering the Fecarbox Featherweight title with a three round knockout win over Jose Luis Velazquez.
May 18 of 1996 at a Showtime televised fight, Vazquez made history twice: He became a member of the exclusive group of world champions in three different categories, and at the same time he was the first boxer in history to win all three different divisions under the auspices of the same organization, when he became the WBA's world Featherweight champion by knocking out Eloy Kiki Rojas in round eleven at Las Vegas. Trailing on all scorecards, Vazquez dropped the champion twice in the last round of the fight to make the referee stop the fight.
He retained the title four times, against Bernardo Mendoza, Yiji Watanabe, Roque Cassiani and Genaro Rios, and then he challenged Naseem Hamed for a unification bout. But the WBA refused to sanction the bout, and so the fight went on, as a WBO world Featherweight championship bout. In his last world title bout, Vazquez was knocked out in round seven by Hamed on April 18 of 1998 in Manchester.
He returned with two wins, then lost to Juan Lazcano by a knockout in nine for the NABF's Featherweight belt on June 16 of 2000.
Vazquez has won all four of his fights since, three by knockout, including his last two, both of which were against Eddie Sainz.
During his title reigns, Vazquez was known as a world traveller, defending his crown in France, Italy, Japan, San Antonio, South Korea and other places. Before his defense against Cermeno, he had said it was his dream to someday defend a world title in his home country of Puerto Rico. To add to his travels, he usually trained in Toluca, Mexico before his fights.
Since 1988, a marathon race named after Vazquez takes place each year in his native Bayamon. The Wilfredo Vazquez International Marathon attracts runners from many countries every year.
His record consists of 56 wins, 9 losses, 2 draws and 1 no contest, with 41 wins by knockout.