While attending New York University, he was discovered by casting director Bonnie Timmerman who saw him in the award-winning student film "Five Out of Six.” Leguizamo made his feature debut in Paul Morrissey's "Mixed Blood" (1984), a French-produced crime comedy shot on New York's Lower East Side, played the recurring role of vengeful drug boss Orlando Calderone in three episodes of NBC' "Miami Vice" and landed his first substantial film part in "Gentile Alouette,” shot in 1985 but shelved until 1990. Leguizamo shone as the no-nonsense drag queen fighting for the man he loves in the expertly rendered short film "Time Expired" and as a sensitive Puerto Rican supermarket clerk undecided whether to attend college in Joseph B. Vasquez's refreshingly intelligent buddy film, "Hangin' With the Homeboys" (both 1991). "Super Mario Bros." (1993), a critical and commercial flop based on the popular Nintendo game, was to have been his entrance into leading man parts, but he fared much better in a small but pivotal role as quintessential slime ball Benny Blanco ("...from the Bronx") in his second film with De Palma, "Carlito's Way" (1994).

TV came calling wanting to package him into a sitcom, but Leguizamo opted for "House of Buggin'' (Fox, 1995), a landmark showcase for his comedic talents. Serving as executive producer, creator, writer and star for what purported to be America's first Latin-American sketch comedy show, he championed the same kind of character-driven humor that had made his one-man off-Broadway shows such hits. Hailed as a Hispanic "In Living Color,” the wildly uneven series received excellent reviews but lackluster ratings. Leguizamo returned to features as one of the three leads in the heavily promoted drag comedy "To Wong Foo, Thanks for Everything, Julie Newmar" (1995). Teamed with Patrick Swayze and Wesley Snipes, he walked away—on high heels, no less!—with the best notices. An old hand at drag, Leguizamo prepared for the role by switching to a vegetarian diet and avoiding the gym. These measures helped him lose muscle tone and gave his skin a soft alluring appearance befitting a dedicated drag queen.

Leguizamo played Wesley Snipe's agent in Tony Scott's "The Fan", getting the chance to act in the same movie with Robert De Niro (who had ventured backstage to congratulate him after a performance of "Spic-o-Rama"), and turned in his macho Latin gangster portrait of Tybalt for Baz Lurhmann's "William Shakespeare's Romeo + Juliet" (both 1996). He co-produced "The Pest" (1997), a sort of "The Deadly Game" meets "Mambo Mouth/Spic-o-Rama", with writing partner David Bar Katz. Hunted by a German guy whose one missing ethnic trophy is 'Latinus Specticus', Leguizamo revisited a variety of characters created in the past, donning the different disguises to throw his adversary off the scent, however the clever vehicle for himself failed to find an audience. That same year, he also endured hours of make-up and the indignity of his prosthetic fat suit to portray the evil Clown, Devil's emissary in "Spawn,” adapted from the Todd MacFarlane comic, garnering the best reviews of the dark, violent, mean-spirited picture.

Leguizamo returned to NYC's P.S. 122, where both his previous one-man productions had their genesis, for "Freak: A Semi-Demi-Quasi-Autobiographical Comedy" (1997). Featuring 39 separate characters, "Freak" opened on Broadway in February of 1998 to much critical praise and earned him two Tony nominations. Claiming to have hidden behind his costumes in "Mambo Mouth" and "Spic-o-Rama,” Leguizamo presented his most personal portrait to date, what he called his "emancipation proclamation." At its center, the violent, frustrating and real relationship with his father gave "Freak" a depth the downtown shows had lacked, but in the end, it was the warm portrait of his mother as a woman who finds her inner strength without a man that gave the material its heart. "Freak" followed the path blazed by his previous one-man shows, becoming a 1998 HBO comedy special, this time with Spike Lee at the helm, weaving the finished product together from tapes of two live performances. Leguizamo later rejoined Lee for the film "Summer of Sam" (1999).

In 2000, Leguizamo took a dramatic role as a mentally challenged young man who witnesses the murder of his mother in "King of the Jungle." He next had a much lighter role in the phenomenal hit "Moulin Rouge" where he played a supporting role to stars Nicole Kidman and Ewan McGregor as Henri de Toulouse-Lautrec. For both of these roles, Leguizamo was nominated for an ALMA award. Leguizamo had a busy year in 2002, appearing in David Goyer's directorial debut "Zigzag" and the Arnold Schwarzenegger actioner "Collateral Damage,” voicing Sid the Sloth in DreamWorks CGI-animated hit "Ice Age," and taking the lead as a drug dealer who makes a poor investment decision in the gritty crime drama "Empire." In 2003, he was set to broaden his horizons by directing his first screen production, "Infamous" for HBO. Leguizamo also starred in the feature about a boxer from Queens who makes it big but must find a way to integrate his fame into his old life.

In the remake “Assault on Precinct 13” (2004), his talents were squandered once again in playing the stereotypical role of a fast-talking junkie who’s forced into defending a police station from murderous cops trying to silence a gang boss who can put them in jail. Leguizamo then appeared in the rehash of the famed 1950’s sitcom, “The Honeymooners” (2005), playing a character not in the original series. Though promising a fresh take on an oldie-but-goodie, the movie was blasted by critics who complained about a lack of chemistry between characters, a subservient bow to political correctness—particularly with Kramden’s famous threat to send Alice to the moon—and a dearth of laughs despite overwhelming comedic talent. He next appeared in George Romero’s “Land of the Dead” (2005), the fourth installment to the “Night of the Living Dead” series, playing a supply mercenary whose rival (Simon Baker) is coerced into protecting a fortified city against a horde of invading zombies.

He next revived Sid the sloth for “Ice Age: The Meltdown” (2006), the wildly successful sequel that reunited Sid, Manny the wooly mammoth (Ray Romano), Diego the saber-toothed tiger (Denis Leary) and Scrat the prehistoric squirrel (Chris Wedge) in a quest to find Manny a mate despite possibly being the last mammoth in their rapidly changing world. He next had a supporting role in the Edward Burns’ “The Groomsmen” (2006), a bittersweet comedy about a groom and his four groomsmen who suddenly realize that their extended adolescence may soon be coming to an end. On the small screen, Leguizamo shot a pilot for CBS called “Edison” (2006- ), a procedural drama in which he played an undercover cop who uses his skills as a con artist to capture criminals, but finds that his compulsive lying hampers his personal life.