The actor will play John Tattersall, "a radical, self-educated surgeon who will go to unorthodox lengths to uncover the secrets of the human body", Deadline reports.
Roth's Fox drama Lie to Me ended its run last year.
Based on Wendy Moore's biography of 18th-century surgeon John Hunter, Knifeman will be produced by Cronenberg alongside Friday Night Lights and Weeds producers Rolin Jones and Ron Fitzgerald.
Cronenberg will also direct the first episode of the series, which has been ordered straight to series by Media Rights Capital, and will be shopped out to networks soon.
Roth recently signed on to the BBC's adaptation of Daniel Clay's novel Broken.
Watch a clip from Cronenberg's Cosmopolis below: