The hospital readies for its move uptown, while Dr. Edwards makes a play to be named permanent chief of surgery and Dr. Gallinger heads over to Cromartie Hospital in hopes of getting Dr. Thackery to come back to work. Bertie rebuffs Lucy's attempt to make amends. Ping Wu demands his prostitutes be given regular medical checkups. Speight tracks a new plague. Cornelia ministers to a quarantined San Francisco neighborhood.

Thackery enlists Edwards to help him test a new hypothesis. After rejecting Robertson’s advances at The Knick, Lucy learns that confession isn’t always good for the soul. Young journalist Genevieve Everidge works on a story about one of Thackery’s rivals. Cornelia is dismayed by the limits of her husband’s sympathies. Barrow faces a new adversary at Tammany Hall. Gallinger is intrigued by a discussion of eugenics at a class reunion. Edwards deals with a surprise visitor.

Abby’s worsening condition persuades Thackery to test out his novel syphilis treatment. Edwards comes clean to Opal, but does not get the response he expects. Cleary makes a last-ditch effort to raise funds for Harriet as her date in court arrives. Bertie undergoes physical training. Barrow loses a sponsor. Gallinger’s prejudices are reinforced. Cornelia probes a suspicious death. Lucy laments her lot in life.

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.

Faced with a quandary, Bertie decides to take matters into his own hands at Mt. Sinai, enlisting Algernon to help. Thackery investigates the efficacy of hypnosis, and takes an interest in a pair of conjoined twins. Lucy lobbies Henry for a gala invitation. Cornelia visits the brother of a deceased immigrant with ties to Speight. Gallinger dines with an unwelcome guest. Barrow previews a new home for Junia. Harriet agrees to make a change.

Fighting his nerves, Thackery readies himself to attempt to separate Zoya and Nika in front of a packed audience. After getting a surprise gift from her father-in-law, Cornelia attends a gala charity ball for the new Knick with other familiar guests. Barrow gets rid of a threat. Opal spoils the Robertsons’ good mood. Algernon gets a long-overdue spotlight in the surgical theater, but complications ensue.

Thackery attempts a new cure in the inebriation ward; Brockhurst demands his "girls" be returned; Gallinger and his wife's relationship and Bertie's relationship with Genevieve go off in surprising directions. Later, Cornelia shows evidence of the company's wrongdoing to Henry; Barrow's marriage troubles come to a head; and Thackery performs plastic surgery on Abby.

Thackery and Capt. Robertson's connection and how the doctor arrived at the Knick, are revealed; the problems between Edwards and Gallinger come to a head after a medical-board hearing about Gallinger's vasectomies. Later, Cleary and Harriet engage in a joint business venture; Lucy shares memories with her father; Barrow realizes the rising costs of living well; and Cornelia and Henry face a family crisis.

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.