John Leguizamo started out as a stand-up comic doing the New York nightclub circuit. In 1984, he made his T.V. debut with a small part in Miami Vice.
In 1991 he also he wrote and took part in the Off-Broadway production Mambo Mouth, where he played seven different characters. Mambo Mouth won an Obie Award and an Outer Critics Award. He was listed as one of 12 "Promising New Actors of 1991" in "John Willis' Screen Worlds Vol. 43".

In 1993, Leguizamo wrote and participated in Spic-O-Rama, where he made fun of the stereotyping of Latinos in the U.S.. The production won a Drama Desk Award and four Cable ACE Awards. The 1993 movie production Super Mario Brothers where he played the role of "Luigi Mario", uplifted his acting career in Hollywood.

In 2000, Leguizamo played two genies in the Emmy Award winning miniseries Arabian Nights. Leguizamo has participated in over 53 films, including The Alibi where he will play the role of "Hannibal" and which is in the post-production stages as of 2005.
Leguizamo also created, executive produced, wrote for, and starred in the 1995 Latino-oriented variety show called House of Buggin'. The show showcased Leguizamo's well-known ability to assume a wide variety of colorful, energetic characters. The show ran less than a year on Fox.

In 1998, he debuted on Broadway in the production of Freak, which was also turned into an HBO film by director Spike Lee. Leguizamo has produced 10 films, including Pi?ero and made 13 TV guest appearances.

Later, in 2003, he voice-acted Globox from Rayman 3. The game versions with his voice acting were PlayStation 2, GameCube, Xbox, PC, and Mac.

In 2005, Leguizamo joined the cast of the show ER, playing Dr. Victor Clemente, a new attending who is keen on introducing the staff of County General to ways of treating patients and cutting-edge technology.