After graduating from Maumee High School in 1977, he attended Northwestern University; during this time, Knepper obtained professional roles in plays in Chicago.

He made appearances on such television series as The Twilight Zone, Star Trek: The Next Generation, ER and Law & Order.

After Prison Break ended in 2009, Knepper was cast as villain Samuel Sullivan in the fourth and final season of Heroes.

The same year, he appeared in R.I.P.D., Percy Jackson: Sea of Monsters and guest starred on the television series The Blacklist (episode: "The Courier").

[10] In 2014, Knepper guest starred in episodes of Arrow and The Flash as master hacker and time-and-motion study expert William Tockman / Clock King.

[11] Beginning in 2015, Knepper had a recurring role on iZombie as Angus McDonough, the estranged and abusive father of Blaine DeBeers (David Anders).

[16] On November 8, 2017, costume designer Susan Bertram accused Knepper of sexual assault on the set of the film Gas Food Lodging in 1991.

[19][20] On February 28, 2018, Bertram's lawyers announced she was filing a defamation lawsuit against Knepper in Los Angeles County Superior Court in the wake of his denials, seeking damages in a jury trial.