As Barrow and The Knick prepare to move uptown, Dr. Edwards lobbies the hospital board to be appointed permanent chief of surgery in Dr. Thackery's absence. Though his suspension has been lifted, Dr. Gallinger refuses to return as Edwards' subordinate, so he heads to Cromartie Hospital in hopes of getting Thackery to return to work. Lucy's attempts to make amends with Bertie are rebuffed; Cleary schemes to make extra money; Ping Wu demands regular medical checkups for his prostitutes; Speight attempts to trace the origins of a new plague; Cornelia nourishes a quarantined neighborhood in San Francisco.
The setting: downtown New York in 1900, a tumultuous time of massive change and great progress. The series centers around the groundbreaking surgeons, nurses and staff at Knickerbocker Hospital, who are pushing the bounds of medicine in a time of astonishingly high mortality rates and zero antibiotics.