In the series premiere of this medical drama set in a 1900s New York City hospital, accomplished Dr. John W. Thackery is named chief surgeon and is pressured by a major benefactor to hire a black doctor as his top assistant.

Already fuming over the hospital's faulty new electrical system, Thackery tasks Herman Barrow, the Knick's crooked superintendent, to deliver more cadavers so that he and his team can test out novel surgical procedures. With more patients dying, Edwards offers to share a procedure he learned in France, but is rebuffed by Thackery and Gallinger. Robertson addresses a typhoid-fever outbreak, Elkins is taken into Thackery's confidence and Sister Harriet breaks a taboo. Edwards finds an alternative way to perform his duties.

During surgery, Thackery's hand is forced by Algernon, which irks Gallinger. A recovering Abigail regrets her involvement with Thackery and Sister Harriet and Cleary make a couple of deals. Meanwhile, Bertie receives a scolding from his physician father who is unhappy with his son's career path and Lucy becomes privy to Thackery's secrets.

After testing out a new procedure, Thackery and Bertie vow to reverse a series of failures in the operating theatre. Euphoric after helping Speight, Cornelia finds herself less than enthusiastic about her status as the future Mrs. Phillip Showalter. Thackery entertains a salesman’s pitch; Everett considers how to help Eleanor with her grief; Barrow haggles over used merchandise. Edwards finds his clinic, and his career, in jeopardy after a surprise encounter.

The stabbing of a cop by a black man stirs up racial tension on the street and in the Knick, forcing Thackery and Edwards to take action. Everett returns to work and a changed OR. Barrow fears for Junia’s safety. Cornelia is impressed with Edwards’ ingenuity and Lucy is escorted home.

Already on edge due to a city-wide run on cocaine, Thackery worries that Dr. Levi Zinberg, a Jewish surgeon and inventor, will steal his spotlight at the next New York Surgical Society presentation. Bertie continues his courtship of Lucy while staving off his father’s persistent demands that he leave the Knick. Cornelia, Speight and Bertie go to court in an attempt to keep “Typhoid Mary” Mallon quarantined. Gallinger tries to get Eleanor to move past her grief.

Dr. Thackery makes a move to return to The Knick, which the board frowns upon. Cornelia gets Cleary to do a dirty job, but it comes with a cost. Robertson makes a push for a new subway initiative. Barrow drives up construction costs. Lucy receives a surprise visitor from home.

A subway explosion leads to an influx of patients at The Knick, but little margin for profit. Pursued by Henry, Lucy takes to heart advice from one of Ping Wu’s girls. An addict’s misfortune gives Thackery an ideal test case for his latest theory on addiction. Bertie submits his adrenalin research to Zinberg. Cornelia gets a new clue in Speight’s death. Barrow repays a debt but gets no credit. Genevieve charms the Chickerings. Harriet finds herself a boarding-house pariah.

Thackery ignores Zinberg's advice at Mt. Sinai and undertakes a risky, alternative course of action; Cornelia confronts Henry about the family business; Barrow's actions at the hospital construction site are called into question; Gallinger ponders a job opportunity; and Cleary steadfastly refuses to give up on Harriet.