De Souza started his film career writing, directing, and producing the low-budget stoner comedy Arnold's Wrecking Co., which won the Special Jury Prize at the 1972 Atlanta Film Festival. Beginning in the early 1980s, he became a prolific Screenwriter of feature films, specializing in blockbuster action and thriller films like Commando and Die Hard. He wrote some of the most successful films of the era, including 48 Hrs., The Running Man, The Flintstones, and Die Hard 2. He was frequently hired by studios as a script Doctor in order to rewrite preexisting screenplays during production to add more action and humor. He has been nominated twice for the Edgar Allan Poe award, an award given to any piece of media for excellence in mystery writing. The first in 1984 for 48 Hrs. and again in 1989 for Die Hard. De Souza also "won" the 1991 Razzie Award for Worst Screenplay for Hudson Hawk. He wrote and directed the 1994 video game adaptation Street Fighter after being introduced to the franchise by his son. Though the film received negative critical reception and failed to spawn an intended franchise, it has since become a cult classic in some circles.

In 2000, he was honored with the Norman Lear Award for Lifetime Achievement in writing. In 2004, he received the Dr. Bird award, which is given for achievement in the arts to people of Jamaican descent. De Souza appeared in the feature-length documentary Dreams on Spec, which profiled three aspiring screenwriters and featured comments from a number of distinguished Writers like James L. Brooks, Nora Ephron, Carrie Fisher, and him. His Web series Unknown Sender became a triple honoree at the 2009 Webby Awards for Best Writing, Best Dramatic Series, and Best Individual Performance.

In 2011, he teamed with Family Guy Director Pete Michels for the Fox Network animated pilot "Spyburbia."