Sizemore was born in Detroit, Michigan, to a mother who was a member of an urban ombudsman staff and a lawyer/psychology professor father, Thomas Edward Sizemore, Sr. He has a younger brother, Paul, who is also an actor and a niece Beverly who is a songwriter and former Pussycat Doll. Sizemore attended Michigan State University for one year, as well as 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 Sizemore's early film roles was in Oliver Stone's Born on the Fourth of July in 1989. He has appeared in films such as Lock Up (1989), Harley Davidson and the Marlboro Man (1991), True Romance (1993), Natural Born Killers (1994) and Strange Days (1995). A succession of well-received supporting parts followed, perhaps the most well known being his portrayal of Michael Cheritto in Heat (1995). His first major leading role was as Vincent D'Agosta in 1997's The Relic.

Sizemore had a recurring role on the television series China Beach (1988 to 1991) as an enlisted man named Charlie who was in love with Dana Delaney's character.

Sizemore continued to play leading and character parts in many films, notably Bringing out the Dead, Saving Private Ryan, HBO's Witness Protection, Red Planet, Pearl Harbor, Devil in a Blue Dress, and Black Hawk Down. He had a voice part as Sonny Forelli in the video game Grand Theft Auto: Vice City. He had a supporting role in Kevin Costner's Wyatt Earp as Bat Masterson. In 2001, Sizemore starred in Ticker, an action film directed by Albert Pyun, with Steven Seagal and Dennis Hopper . 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. He also played an undercover cop in the film Swindle opposite Sherilyn Fenn.

Sizemore fronted the Hollywood rock band Day 8. Formed in 2002, the band recorded a 4-song EP produced and recorded by former Snot/Soulfly guitarist Mikey Doling. The group included Rod Castro, Tyrone Tomke and Michael Taylor.

In 2004, he starred in the movie Paparazzi and in the 2006 film, The Genius Club, playing a terrorist who taunts seven geniuses into solving the world's problems in one night.

In 2007, the television network VH1 aired a six episode reality TV series called Shooting Sizemore, which depicted the life of the actor as he struggled to regain his career in the midst of a continuing battle with addiction. The series also covered an ongoing legal appeal on his conviction for an assault of former Hollywood madam Heidi Fleiss. In 2008, Sizemore appeared in The Last Lullaby, playing a killer, and in the thriller film Red with Brian Cox.

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 was then sentenced to 17 months in jail and four months in drug treatment for repeatedly failing drug tests while on probation on March 25, 2005. On June 3, 2005, Sizemore filed a writ of habeas corpus to appeal his conviction of domestic violence against Fleiss, accusing 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.[citation needed] Dabrizzi never took the stand and Sizemore's attorneys say they were unable to locate anyone with that name. Fleiss allegedly contradicted herself in a civil trial by saying she didn't know who took the photo, according to the Superior Court petition.

On August 18, 2005, approximately eight hours of celebrity sex tape starring Sizemore was published on the internet. The material has since become available on DVD.

On May 8, 2007, while still on probation for a previous drug conviction, Sizemore was again arrested outside the Four Points Sheraton hotel in Bakersfield, California. Police found what appeared to be two bags of methamphetamine and three meth pipes in his 2004 Ford Mustang. Police were called after paroled dealer Jason Salcido challenged a hotel employee to a fight after being refused check-in. Police found a meth pipe on Salcido and found Sizemore waiting in his car outside the hotel. On June 25, Sizemore was sentenced to 16 months, but the sentence was reduced to nine months because he had already served 213 days behind bars. He is not related to Cleveland Indians centerfielder Grady Sizemore.

• Lock Up (1989)
• Rude Awakening(1989)
• Penn & Teller Get Killed(1989)
• Born on the Fourth of July(1989)
• Blue Steel (1990)
• Flight of the Intruder(1991)
• Guilty by Suspicion (1991)
• Point Break (1991)
• Harley Davidson and the Marlboro Man(1991)
• A Matter of Degrees(1991)
• Where Sleeping Dogs Lie(1992)
• Passenger 57 (1992)
• Watch It(1993)
• Heart and Souls(1993)
• Love Is Like That (1993)
• True Romance(1993)
• Striking Distance (1993)
• Wyatt Earp(1994)
• Natural Born Killers(1994)
• Devil in a Blue Dress(1995)
• Strange Days(1995)
• Heat(1995)
• The Relic(1997)
• Saving Private Ryan (1998)
• Enemy of the State (1998)
• The Florentine (1999)
• The Match(1999)
• Witness Protection (1999)
• Bringing Out the Dead(1999)
• Play It to the Bone(1999)
• Get Carter(2000) (voice only)
• Red Planet(2000)
• Pearl Harbor(2001)
• Ticker(2001)
• Black Hawk Down (2001)
• $windle (2002)
• Welcome to America(2002)
• Big Trouble (2002)
• Pauly Shore Is Dead (2003)
• Dreamcatcher(2003)
• Hustle (2004)
• Piggy Banks(2004)
• Paparazzi (2004)
• No Rules(2005)
• The Nickel Children(2005)
• Furnace(2006)
• Bottom Feeder (2006)
• Zyzzyx Road (2006)
• Ring Around the Rosie (2006)
• Shut Up and Shoot! (2006)
• Splinter (2006)
• The Genius Club(2006)
• Superstorm (2007)
• White Air (2007)
• A Broken Life(2007)
• Commute(2007)
• Protecting the King(2007)
• Oranges(2008)
• The Flyboys (2008)
• Stiletto(2008)
• The Grind(2008)
• Toxic(2008)
• Red (2008)
• American Son (2008)
• The Last Lullaby (2008)
• Double Duty(2008)
• Shadows in Paradise (2008)
• Super Capers(2008)
• Corrado (2008)