Guzman began acting in a high school production of "Bye Bye Birdie", and went on to appear in street theater and local productions while working as a social worker at the Henry Street Settlement House in downtown Manhattan. Guzman made his film debut with a lead in Bette Gordon's independent feature, "Variety" (1983), a feminist investigation into the porn industry. Playwright and screenwriter Miguel Pinero urged him to audition for a spot on the NYC-set second season opener of "Miami Vice" (NBC, 1985). Guzman subsequently became a steady supporting player with feature credits including "True Believer" as a convict who testifies against lawyer James Wood's client, Robert Wise's "Rooftops" (both 1989) as an abusive father, and "Mr. Wonderful" (1993) as a friend and co-worker of power company employee Matt Dillon. His TV credits include TV-movies and guest shots on "Law & Order", "Homicide: Life on the Street", and "Seaquest DSV". Guzman later had major supporting roles in two high-profile productions: Brian De Palma's "Carlito's Way" (1993) as Al Pacino's ambitious right-hand man, and "The Cowboy Way" (1994) as a fellow who smuggles in Central Americans to work in US sweatshops.

As adept at playing comedy as he is portraying menacing street characters, Guzman (pronounced "Goose-man") quickly became one of Hollywood's most in-demand character actors. He particularly attracted the attention of two leading directors, Steven Soderberg and Paul Thomas Anderson, who quickly added Guzman to stable of actors who appear as part of both directors' unofficial "repertoire companies". Soderberg cast the actor in his films "Out of Sight," "The Limey," "Traffic" (for which Guzman won a Screen Actors Guild award as part of the film's ensemble for Best Performance by the Cast of a Theatrical Motion Picture) and the Soderberg-produced "Welcome to Colinwood". Anderson put Guzman in his films "Boogie Nights," "Magnolia" and "Punch-Drunk Love." He also appeared for several seasons as inmate "El Cid" on the HBO prison drama "Oz."

Guzman was convincing as Jacopo, loyal servant to Edmond Dantes, in “The Count of Monte Cristo” (2003). A serviceable adaptation of the Alexandre Dumas classic tale of adventure, director Kevin Reynolds tried to elevate a swashbuckling tale of revenge into something more elegant. Guzman made a couple uncharacteristic missteps, appearing in the dreadful Eddie Murphy space comedy, “The Adventures of Pluto Nash” (2003) and the equally abysmal “Dumb and Dumberer: When Harry Met Lloyd” (2003). Both died ignominious deaths at the box office, but Guzman suffered no permanent damage to his career. In “Anger Management” (2003), Guzman appeared as a member of a group therapy session who help unleash Adam Sandler’s hidden rage.

After playing a corrupt cop who joins a scam operation in “Confidence” (2003), a little-seen crime drama with Edward Burns and Rachel Weisz, Guzman joined Jim Carrey in “Lemony Snicket’s A Series of Unfortunate Events” (2004), adapted from the popular children’s novels also loved by adults. In the low-budget slice-of-life comedy “Waiting” (2005), about a waiter (Justin Long) who rues his dead-end life, he played a cook at a restaurant who likes to do disgusting things to himself and the food.