During Arkham Origins, Harleen's outfit was much more sensible than that of the later games, as she was working at Blackgate Prison and hadn't started her dark life of crime. Her uniform consisted of colors similar to her outfits as Harley yet lacked a lot of the design elements. Harleen’s hair was in a bun, with her hair pushed to the left side of her face, instead of the trademark twin ponytails. She wore a white coat over a red blouse, with her name tag pinned on the left side of her chest. She wore black pants and a black skirt, with black stockings and red heels.

During her early life, Harleen had a criminal father who gave her distorted morals, but also led her to become fascinated by the extreme criminal mind. Being academically intelligent, she therefore undertook a psychiatric medical degree at Gotham City University as this was the quickest method of being able to treat criminal behavior in institutions such as Arkham Asylum. While at the university, Harleen may have developed her skills in gymnastics

By the time of Christmas Eve, Quinzel was nearly finished with her psychiatric residency at Blackgate. After Julian Gregory Day, also known as the serial killer Calendar Man, was arrested by the GCPD with the anonymous help of Batman, Quinzel did a psychological evaluation of the serial killer, and determined that Day was insane and thus could not be executed. However, Warden Joseph had her redo the evaluation under the pretense that he was manipulating her (although, it was heavily implied that Joseph himself was being manipulated by Commissioner Loeb into having Day ruled sane and execute him to gain political points). She did so under the condition that she be allowed to do psychiatric evaluation on all new prisoners from that point onward.

Harleen appeared when Joker got captured by the GCPD at the Royal Hotel and was sent to Blackgate, where she performed a psychological assessment on him, by using assessments such as word association. During their session, Joker described the encounter between him and Batman and stated that it had changed the way he thought, but he never specified that he was talking about Batman. Harleen therefore thought that Joker was talking about her, so, she grew an affinity toward her patient.

Harleen was seen again at the Blackgate Riot later that night where she was held hostage by a group of ten escaped Blackgate Prisoners in the Nexus. Batman quickly intervened, but Quinzel showed no form of gratitude toward her savior, nor did she show signs of shock from being almost killed. When Batman asked Quinzel if she was alright, she replied: "What's it to ya?" Harleen walked away from Batman as he stated that: "You were almost killed." She then replied back: "Eh, occupational hazard." And revealed that the Joker was located inside the Panopticon, and that he was waiting for Batman's arrival.

Harleen was seen for the last time with a group of guards escorting the Joker to a cell at Blackgate, who laughed at Batman's deception. As Harleen walked alongside him, Joker stated his belief that his future battles with Batman would indeed be "fun" - possibly already set on the idea of the prison takeover attempt during the Arkham Origins Blackgate Incident three months later.