Born in Detroit, Michigan, Sizemore attended Michigan State University for one year, Wayne State University and earned a Master's Degree in theater from Temple University in 1986. He subsequently moved to New York City to pursue an acting career. One of his first film roles was in Oliver Stone's Born on the Fourth of July in 1989. He has also appeared in films such as Harley Davidson and the Marlboro Man (1991), True Romance (1993) and Natural Born Killers (1994). A succession of well-received supporting parts followed, the most well known being Michael Cheritto in Heat (1995). His first major leading role was as Vincent D'Agosta in 1997's The Relic.

Sizemore continued to play leading and character parts in many films, notably Saving Private Ryan, HBO's Witness Protection, Red Planet, Pearl Harbor, and Black Hawk Down. He also had a voice part in the video game Grand Theft Auto: Vice City.

In 2002, Sizemore starred in the well-reviewed but short-lived television drama series Robbery Homicide Division. It was cancelled mid-way through its first season.

In 2004, he starred in the movie Paparazzi.

Sizemore, who had long battled drug addiction, was convicted in 2003 of assault and battery against his girlfriend, the former “Hollywood Madam” Heidi Fleiss. Sizemore has been sentenced to 17 months in jail and four months in drug treatment for repeatedly failing drug tests while on probation on 25 March 2005. On 3 June 2005, Tom filed a writ of habeas corpus to appeal his conviction of domestic violence against Fleiss.

Sizemore accuses Fleiss of faking a picture of her bruises submitted as evidence during the April 2003 trial. Fleiss testified the photo was taken by a friend named Tara Dabrizzi who left the next day to visit her ailing mother in another country. Dabrizzi never took the stand and Sizemore's attorneys say they were unable to locate anyone with that name. Fleiss, Sizemore's ex-girlfriend, allegedly contradicted herself in a civil trial by saying she didn't know who took the photo, according to the Superior Court petition.

Sizemore had other well infamous publicized run-ins with the law. He was caught using a fake penis sewn into his boxer shorts and filled with a clean urine sample kept warm by a heating pack to fool his drug tests. The temperature of the urine sample proved too cool to have come from his body, and he was asked to remove his pants. Sizemore had been caught once before trying to use a similar device, sold over the Internet under the brand name the “Whizzinator”, and had failed drug tests on at least five occasions. Sizemore failed two drug tests on the days following the fake penis incident showing he had methamphetamine in his system.

On 18 August 2005, approximately eight hours of Celebrity sex tape starring Sizemore were published on the Internet by a company named ifreeloader.