In 1900 New York City, renowned surgeon Dr. John Thackery awakes in an opium den. He makes his way over to the Knickerbocker Hospital where he works, but not before injecting cocaine into his foot.
Upon his arrival, Thackery and the head of surgery, Dr. J.M. Christiansen, scrub in to operate on a pregnant woman with a case of placenta previa. They work alongside Dr. Everett Gallinger, Dr. Bertram "Bertie" Chickering Jr., and Nurse Monk in a crowded surgical theater. This is their twelfth attempt at the procedure, and for the twelfth time, both mother and child die.
Following the surgery, Christiansen retires to his office, pulls out a revolver, and takes his own life. Thackery gives a rousing eulogy at his friend's funeral, pledging to continue pushing the medical field into the future.
At the hospital board meeting, the hospital's manager, Herman Barrow, enumerates its rising costs. Thackery takes Christiansen's place as Chief of Surgery, leaving an opening for a deputy. Thackery believes Gallinger is the man for the job, but Cornelia, the daughter of the hospital's benefactor Captain Robertson, insists on a new candidate - a highly-accomplished surgeon named Algernon Edwards, recently returned from Europe.
Algernon meets with Thackery, who is surprised to discover that the candidate is black. Thackery insults him and rejects him out of hand. Cornelia insists that Thackery take him on, and when the doctor refuses, the Robertsons pull their funding for the hospital's electrification. To keep the lights on, Barrow tells Algernon and the other doctors that Thackery has hired him.
Tom Cleary, the hospital's rough-and-tumble ambulance driver, accompanies health inspector Jacob Speight and police officer Phinny Sears to a Lower East Side tenement to pick up a woman with tuberculosis. They bring her to the Knick where, with the woman's daughter translating, Cornelia tells her she's going to die. Speight hits up Barrow for payment as a reward for steering the patient to the Knick - along with the city's funding of her stay.
One of Gallinger's patients suffers from a post-surgical infection as well as bronchitis. Thackery is needed for surgery, but is nowhere to be found. Lucy Elkins, a young nurse, is sent to retrieve him from his house, where she finds the doctor suffering from crippling cocaine withdrawal. As the veins in his arms have collapsed, he has Lucy inject the drug directly into his penis.
Thackery, suddenly functional and alert, prepares for surgery. Having anticipated the infection, Thackery produces a clamp he forged in the hospital's furnace. He performs the revolutionary operation in front of a stunned audience. Afterwards, Thackery invites Algernon to resign, but the junior doctor refuses. "I'm not leaving this circus until I learn everything you have to teach," he says.
With Algernon staying on, the hospital's electrification process resumes.