Set in downtown New York in 1900, 'The Knick' is centered on the Knickerbocker Hospital and its staff, notably Dr. John Thackery, the hospital's brilliant chief surgeon who pushes medicine's boundaries, pioneering new procedures despite a severe drug addiction.

Raymond "Red" Reddington, one of the FBI's most wanted fugitives, surrenders in person at FBI Headquarters in Washington, D.C. He claims that he and the FBI have the same interests: bringing down dangerous criminals and terrorists. In the last two decades, he's made a list of criminals and terrorists that matter the most but the FBI cannot find because it does not know they exist. Reddington calls this "The Blacklist". Reddington will co-operate, but insists that he will speak only to Elizabeth Keen, a rookie FBI profiler.

A failed New York playwright stages a suicide in an attempt to win back her ex, only to wind up in the custody of her gambling-addict mother.