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.