Fichtner graduated from Maryvale High School (Cheektowaga) in 1974. After graduating from Farmingdale State College in 1976 with an associate degree in criminal justice, he attended SUNY Brockport and earned a Bachelor of Arts degree in criminal justice in 1978. He then studied at the American Academy of Dramatic Arts in New York. He also credits his Farmingdale State College admissions counselor Don Harvey with his decision to study acting. Harvey, who became a lifelong friend, took Fichtner to his first Broadway show. On May 18, 2008, he was awarded an Honorary Doctorate of Humane Letters by Farmingdale State College.

Fichtner began his acting career as Josh Snyder in As the World Turns in 1987. He has since appeared in the films Contact, Heat, Armageddon, Go, Equilibrium, Black Hawk Down, The Perfect Storm, The Longest Yard, Crash, Ultraviolet, Drive Angry and The Dark Knight. Mainly a character actor, one of his few leading roles is in Passion of Mind, also starring Demi Moore and Stellan Skarsgård. His role in Crash won him a Screen Actors Guild Outstanding Performance Award and a “Best Acting Ensemble” Award from Broadcast Film Critics Choice. He currently appears in the sitcom Mom on CBS.

Credited as Bill Fichtner, he voiced Ken Rosenberg in the video games Grand Theft Auto: Vice City and Grand Theft Auto: San Andreas. Between 2005 and 2006, he also starred in the sci-fi TV series Invasion as Sheriff Tom Underlay. After Invasion was canceled, he played ruthless FBI Agent Alexander Mahone in three seasons of Prison Break (2006–2009). In 2009, he co-presented the Vezina Trophy (for goal tending) at the National Hockey League awards show. He later guest starred as judge Christopher Mulready in The West Wing episode “The Supremes.” He also had a role as the Gotham National Bank manager in the feature film The Dark Knight and as Jurgen in Equilibrium.

In June 2009, Fichtner had a recurring role as TV producer Phil Yagoda on Entourage. He also voiced Master Sergeant Sandman in the 2011 video game Call of Duty: Modern Warfare 3.