In 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. Sister Harriet breaks a taboo. Edwards finds an alternative way to perform his duties.
Thackery weighs performing surgery on a former flame, and orders Gallinger and Chickering to experiment on pigs. Barrow goes to extremes in order to pay off a debt and recover a missing tooth. After a bad day at work, Edwards takes out his frustrations at a local bar. Robertson is relieved when her pleas about treating a patient with typhoid fever are finally heard.
Edwards forces Thackery’s hand during surgery, angering Eleanor. In recovery, Abigail regrets her past choices involving Thackery. Cleary and Sister Harriet strike one deal, then another. Bertie’s father, Dr. Bertram Chickering, Sr., scolds him for his career choices. Lucy learns of Thackery’s secret life.
Barrow looks to pay down a debt by treating one of Collier’s wounded men at the Knick, and tries to convince Captain Robertson to invest in a new Edison invention. Still marginalized by Thackery, Edwards attempts to improve on a hernia surgery. Everett and Eleanor fear for their baby’s health. Cleary and Sister Harriet visit Chinatown.
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. 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.
A late-night crime sheds unfavorable light on the Knick, forcing Robertson to come up with hush money. Lucy goes to extremes to get drugs for an increasingly desperate Thackery, whose plea for an advance from a seller of patent medicines falls on deaf ears. Gallinger despairs as Eleanor’s behavior becomes more erratic. Cornelia and Edwards proffer different solutions to a shared dilemma.
Refusing to collaborate with Dr. Zinberg on blood-transfusion research, an increasingly paranoid Thackery pushes himself to the limit, and beyond, in an effort to “solve the riddle” and beat his rival. Cornelia and Edwards arrive at a crossroads. Barrow trades one creditor for another. Lucy requests Bertie’s help. With the Knick in the midst of yet another crisis, Robertson calls for a vote.
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.
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.
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.