Described as having a genius-level IQ, Harleen attended Gotham State University on a scholarship for gymnastics, where she majored in Psychiatry under Dr Odin Markus. To get into the graduate program, she had Dr Markus meet with her in her dorm room, where she outlined what she believed would be a good graduate thesis: 'There are only two circumstances under which a person disregards the rules of society. When they commit a crime, or when they're in love.' To prove this thesis, she aimed to allow Dr Markus to observe an independent experiment on the matter. The test subjects: herself and her boyfriend Guy Kopski.
Guy, also a scientist, had developed a 'Think Drink' to calm and centre himself. One day, while meeting with Harley, he noticed that she wasn't laughing at any of his jokes. She explained that she had driven through a red light in a stolen car, right after blackmailing Dr Markus and possibly shooting him. She asked if he still loved her, but after noticing evidence of a recently fired handgun, Guy ran out with it. Harleen found him in the gymnasium (where the shooting had supposedly taken place) laughing nervously, and standing over a homeless man he had just shot, believing him to be Dr Markus. He begged her to help him shoot himself, asking her to do it because she loved him. The gun fired, but it remains a mystery as to whether she had helped to pull the trigger.
It later became clear that Dr Markus had spiked Guy's 'Think Drink' with diluted Joker Venom, in hopes of counteracting the stresses that Harley would put him through. Harley, however, believed that the situation had been caused by chaos, and as such, she grew to feel that she understood The Joker, and declared to Dr Markus that she would do anything to get an internship at Arkham Asylum.
Upon graduating, and with a glowing reference from Dr Markus, Dr Harleen Quinzel began her first-year residency at Arkham. As soon as she was accepted by Dr. Arkham, she requested to meet the Joker. Based on the claim that she was doing research for a book on serial killers, she was given complete access to the Clown-Prince of Crime.
In their first session together, she introduced herself as Dr Harleen Quinzel, but stressed that he could refer to her as Harley Quinn, like the medieval jester Harlequin. Joker had been silent until then, but he suddenly began laughing and asked if she was flirting with him. When she moved closer, he chose to strangle her. But, when he saw a loving look from Harley instead of shock or fright, he ceased, and stated that it was a joke. The pair shared an affair, with Quinn helping Joker escape from Arkham several times before she herself was finally caught. Her medical license was revoked and she was committed, despite her claims that all of the releases were meant to be therapeutic.
Harley broke out of Arkham multiple times in order to join up with her The Joker, whom she referred to as "Puddin'." Eventually, though, she acknowledged his abusive behaviour and broke off from him. She decided to become a crime boss on her own, and gathered a gang together that she called The Quintets. After a run in with The Riddler at Wayne Manor during a looting, and a few other failed heists, one of the Quintets decided that Harley should be eliminated. Word was put out that there was a price on Harley's head, and many assassins came to collect it. Killer Croc attacked her in her own secret hideout, but he was subdued thanks to her knowledge of the building. The traitor revealed himself, and would have killed her, if not for the timely intervention of Matches Malone.