De Jesus debuted as a professional in 1969, beating El Tarita by a knockout in three in San Juan. He won his first 20 fights, 13 by knockout, and then he stepped in class for the first time, when he boxed future world title challenger Josue Marquez in 1971, and beat him by a ten round decision. His next fight was against Victor Ortiz, a knockout win for de Jesus in four rounds. After that, there was a rematch with Marquez, who was beaten again, this time over 12 rounds.

Next came his first international fight, in Caracas against the future 4 time world title challenger Leonel Hernandez. De Jesus won that fight by a decision in 10, in what was the start of a 4 fight tour of Venezuela. That Vebezuelan campaign ended with a ten round decision loss against former world champion Antonio Gomez, also at Caracas.

1972 was pivotal for De Jesus' career. He won six fights in a row, including a 12 round knockout win in a third fight with Marquez, and a ten round decision over Doug McClendon. Despite all those wins, he was virtually an unknown boxer to most boxing fans. That changed quickly in his last fight of '72, against the undefeated new world's Lightweight champion Roberto Duran, at the Madison Square Garden arena. In a televised bout that marked the beginning of the Duran-De Jesus trilogy, De Jesus dropped Duran in round one and went on to inflict Duran's first defeat with a ten round decision.

In 1973, he was rewarded for his efforts, receiving a chance to challenge Ray Lampkin for the regional US lightweight belt. He became the United States' champion by beating Lampkin by a 12 round decision. Then, he beat Johnny Gant, by a ten round decision, and Raul Montoya, also by decision in ten. Then, there was a rematch in New York with Lampkin, whom he beat again, by a decision. He finished '73 with a first round knockout win over fringe contender Al Ford.

He began 1974 by knocking out former world Jr. Welterweight champion Alfonso Peppermint Fraser in 10 rounds in San Juan, after which he travelled to Panama City to receive his first world title shot, and at the same time, face Duran in the second fight of their trilogy. He once again dropped Duran in round one, but this time Duran recovered, and retained the title by a knockout in eleven rounds. He recovered from that defeat with two more wins before the end of the year.

In 1975, he went up in weight briefly, and after beating Jesse Lara by a knockout in three, he returned to Panama City to challengeColombia's Antonio Cervantes for the world's Jr. Welterweight title, losing by a 15 round decision. He beat Rudy Barros by a knockout in five to end that year, and he started 1976, by beating Valentin Ramos by a knockout in two.

Next came his third world title try, when the WBC's world Lightweight champion Itshimatsu Suzuki of Japan travelled to Puerto Rico to defend his title against De Jesus. The third time proved to be the charm for De Jesus, who won the world title by beating Suzuki by a 15 round decision. Then, he retained the title against Hector Medina by a knockout in seven.

De Jesus as a world champion started dabbling in drugs, an element which would later threaten to ruin his life, and definitely changed it.

In 1977, he retained the title against Buzzaw Yamabe by a knockout in six, and against Vicente Mijares Saldivar by a knockout in eleven.

1978 began with the third and final chapter of his trilogy with Duran. In a title unification bout in Las Vegas, De Jesus lost to Duran by a knockout in round 12.

De Jesus rebounded with three wins before the end of that year, including one over former world title challenger Edwin Viruet.

In 1979, he had two more wins, including one over Jimmy Belvins. After beating Jose Vallejo by a knockout in seven in San Juan to start 1980, he travelled to Bloomington, Minnesota to challenge Saoul Mamby for Mamby's WBC world Jr. Welterweight title, in the major supporting event of the Larry Holmes-Scott Le Doux world Heavyweight championship bout's undercard. In what turned out to be his last fight, he was beaten by a knockout in thirteen rounds.

His record was 57 wins and 5 losses, with 32 wins by knockout.