Throughout his career, Mondesí exhibited obvious physical gifts of speed, power and a rocket arm (one of the best in baseball history, often compared favorably with that of Roberto Clemente), which were offset by poor plate discipline and attitude issues. Despite his sometimes surly behavior, Mondesi would always hustle and often make a "big turn" at first base even when he had no chance of obtaining a double. He seemed most at home when in the field, where his dead run into "belly buster" dives were a favorite of Dodger Stadium fans.
After beginning his major league career on July 19, 1993 with the Dodgers, for whom he played during seven seasons, Mondesí played for the Toronto Blue Jays, New York Yankees, Arizona Diamondbacks, Pittsburgh Pirates, Anaheim Angels, and Atlanta Braves.
In 2003, Mondesi hit a respectable .272 with 24 HR and 71 RBI with the Yankees and Diamondbacks. However, his career was clearly on the decline when he signed with the Pirates in February 2004. By May he was talking of leaving the team for personal reasons in the Dominican Republic, later known to be threats from hitting instructor Mario Guerrero. He left the team on May 11, 2004 and his contract was terminated a week later, and after another 10 days, he signed with the Anaheim Angels. The deal was investigated by Major League Baseball, as the circumstances were questionable, but the Angels were cleared of any wrongdoing. Shortly after he signed with the Angels, he tore his quadricep and was placed on the disabled list. He was released by the Angels in July for not showing up for his rehab therapy. The Atlanta Braves signed Mondesi as a reclamation project in 2005 and proved once and for all that he was no longer a Major League caliber player, appearing in just 41 games and hitting 4 home runs.
In May 2006, running on the ticket of the Dominican Liberation Party, he was elected to a seat in the Dominican Republic's Chamber of Deputies, representing his home province San Cristobal. In November 2007, he switched sides aligning himself with the Dominican Revolutionary Party after discrepancies with the government over humanitarian aid to be given to his province after Tropical Storm Noel.