As Dr John Thackery becomes the chief surgeon at the Knickerbocker Hospital in New York in 1900, he finds himself facing a tough challenge, as he must handle various obstacles while battling his own cocaine addiction.
Thackery asks the hospital's corrupt superintendent, Herman Barrow, to bring him more cadavers to be able to test out new surgical procedures. After Thackery and Everett reject Algernon's attempt to share a method he learned in France, he finds another way to do perform his work.
When Thackery's old friend, Abbie Alford, asks him to help her after her face was disfigured, he sets out to perform a skin graft. Dr. Edwards struggles with limited resources while trying to open a treatment center for black patients.
Thackery explains to Dr. Edwards that he's only invited into the surgical theater to help Dr. Gallinger with the procedure. Herman Barrow crosses all ethical lines in order to make more money. Cleary and Sister Harriet become partners, as he will be in charge of bringing her future clients.
When one of the pimps of gangster Bunky Collier injures his leg, Thackery is asked to perform the surgery. As Edwards continues to perform his experiments, he goes to the Robertson home when his mother falls ill.
Thackery invites Dr. Chickering to experiment with a new method to reduce the bleeding while performing a Cesarean section. Mrs. Gallinger grieves after losing her baby girl. Cornelia and Speight find a new lead that helps them find the source of the typhoid outbreak.
After a clash with a police officer leads a black man to stab him, a riot breaks out. The staff of Knickerbocker faces an emergency situation, as they struggle to treat the black people who got injured in the clashes.
Bertie continues to pursue Nurse Lucy who's having an affair with Thackery. Thackery struggles with withdrawal symptoms after he is unable to get more cocaine. The judge releases Mary Mallon after she makes a petition to be set free.
The Knick continues to struggle with the aftermath of the cocaine shortage and recent clashes. Dr. Thackery's addiction becomes known after a reckless action exposes his secret. Dr. Algernon rebuffs his lover Cornelia when she seeks his help.
Thackery's drug addiction makes his life spiral out of control as he becomes unable to perform. When Dr. Levi Zinberg is attempting to categorize blood into types, Thackery tries to beat him to it. Cornelia is trying to have an abortion.