After Allen had a son at the age of 18, the twins dropped out of high school and soon began working on music videos as teenagers, directing for artists like Tone LOC and Tupac Shakur. Their first feature film, 1993's Menace II Society premiered at the Cannes Film Festival. Centering on black, disenfranchised youth, it was made on a budget of $3.5 million when they were 20 years old. Tyger Williams wrote the screenplay, and shared story credit with the brothers. It became a critical as well as a box office success and was nominated for an Independent Spirit Award for Best First Feature. Because of their previous experience in directing music videos, they became the first sibling duo since Jerry and David Zucker allowed a waiver by the Directors Guild of America to take co-credit as Directors.

Known as much for their frank manner as for their films, the Hughes Brothers have been known to get into altercations. They took the rap Artist Tupac Shakur to court in 1994, after he assaulted them during a music video shoot. Shakur had originally been slated to star in Menace II Society, but was replaced after the incident that apparently stemmed from Shakur's disliking the role they had chosen for him. He was later sentenced to 15 days in jail for the assault as well as another incident that occurred a day before his sentencing.

Their second film was Dead Presidents in 1995. Dealing with the black underclass society like their feature film debut, and also starring Larenz Tate, the film centered on war veterans during the racially charged Vietnam War era. The film, which was released at the New York Critics Film Festival, failed to make as much of a profit as their first film. They followed Dead Presidents with American Pimp, a feature-length documentary about the underground pimp culture and exploitation of women. It premiered at the 1999 Sundance Film Festival. They had originally set out to do an adaptation of Iceberg Slim's novel Pimp, but someone else acquired the rights. The brothers have stated that the film's perspective was partially shaped by being raised by their mother, who is a feminist. In between projects, they filmed several anti-handgun public Service announcements.

Their only film together since 2001's From Hell was the post-apocalyptic drama Book of Eli for Warner Bros., which was released in January 2010.

Allen has a son with singer/songwriter Stephanie "Stevvi" Alexander, Eric Alexander-Hughes. Albert has a daughter, and has been living in the Czech Republic since 2004.

In 2005, it was announced that Albert would direct a feature film called Art Con, although no further news was reported on its development.

In 2006, the brothers were announced as directing The Iceman, a film about serial killer Richard Kuklinski, but it was eventually directed by Ariel Vromen, and released in 2012. They were also slated to direct a film version of the classic TV series Kung Fu. It was announced in 2010 that the brothers were tapped to direct a live-action adaptation of the 1988 manga Akira, but they left the project in 2011.

In 2009, Allen directed a segment of New York, I Love You, starring Drea De Matteo and Bradley Cooper.

In December 2012, Albert Hughes announced that he would be producing an online video series using the Crysis 3 game engine called The 7 Wonders of Crysis 3.

In a 2013 interview, Albert stated that the brothers "love each other", but are also "kind of in a weird dance right now".