The series was originally conceived under the title Nurse Mona, a considerably darker version of the show with vague supernatural elements, inspired by stories an ER nurse told to executive producer Caryn Mandabach.

Writers Liz Brixius and Linda Wallem had previously written a Showtime pilot about addiction called Insatiable, and were brought on to rework Nurse Mona into a more comedic show, which became Nurse Jackie.

Edie Falco initially passed on the project before becoming intrigued by the main character and ultimately signing on to star.

The story of Jackie's addiction was deeply personal, as Edie Falco, Linda Wallem, and Liz Brixius were all recovering alcoholics themselves.

Actor Stephen Wallem, who plays Jackie's confidant Thor, is the real-life brother of series co-creator Linda Wallem.

After the fourth season, showrunners Wallem and Brixius, who had previously been in a relationship, departed amid major disagreements that were reportedly affecting production; Clyde Phillips took over as showrunner for season five.

Writer Liz Flahive recalled that the show's writing staff was majority female and about half consisted of individuals from the LGBTQ community.

A Dutch remake of the series titled Charlie began airing on Nederland 3 on March 13, 2013, starring Halina Reijn, Katja Schuurman, and Benja Bruijning.