- "In case you Ain't Figured Out, Todays The Joker's Big Home coming and YOU'RE The Guest Of Honour!"
- ―Harley To Batman On A Video
Whilst Batman was escorting the Joker through the Intensive Care unit of Arkham Asylum, Harley was already in the security control room. As the Joker broke free, she opened the adjacent security field allowing him to escape Batman and implement his takeover of Arkham. The Joker then proceeded to release all his followers from their cells to attack Batman. Harley then took Warden Quincy Sharp hostage, taking possession of his decorative cane as well as wearing his warden identification card, and contacted Batman via monitor. She claimed that the Joker was now in charge of the island and she was substituting for Sharp as warden. She also told Batman that Joker was having a homecoming party with Batman as the guest of honor. Batman gave Harley one chance to surrender, which she refused before smashing her monitor with Sharp's cane, cutting off the feed. When Batman made his way to the elevator shaft, Harley appeared, stating that the Joker didn't need to see Batman just yet. She proceeded to blow up the elevator cord, causing the elevator to crash to the floor below and sending herself to the top, nearly killing a security guard named Henry Smith had Batman not saved him. Harley then regrouped with Frank Boles, who had taken Commissioner Gordon hostage. She and Boles proceeded to secure the front entrance of the Intensive Treatment Center and fight off the guards with an army of Blackgate prisoners. After Boles, who had outlived his usefulness, had been disposed of by the Joker, Harley took Gordon and carried on without him.
Quinn, with Gordon, made her way to the Batmobile first, ordering her goons to break into it. She then proceeded to the Medical Center and sat in the main entrance with Gordon tied to a bench by her, relaxing during her "me time". Batman eventually tracked Gordon to the entrance and found Harley humming to herself, but was unable to reach her due to a energy security gate blocking her. Spotting Batman as he walked in, she told him to scram. He asked where Gordon was, to which she replied "Wouldn't you like to know?". Gordon then shouted to Batman, and Harley told him to shut up and threw a glass mug at him. He called Harley a "crazy bitch", and Joker contacted Harley via monitor. He yelled at her, and she squealed in a startled tone. Joker asked why Batman was in the Medical Center, as it was "too early". Harley apologized and kissed Joker through the monitor, asking him not to be angry with her. He then said "You little minx! I could never stay mad at you!" and turned off the monitor. Harley then said that Batman needed to find another way in and bid him farewell, cartwheeling out of the room. She took Gordon to Bane's holding area, given orders by the Joker to kill Gordon if anyone spotted Batman nearby.
Batman followed a trail of tobacco left by Gordon to the Medical wing, defeating Harley by crashing through the glass ceiling above her, and rescuing Gordon. Harley, however, evaded capture after Bane attacked Batman. Harley made her way back to Warden Sharp and followed Batman to Arkham Mansion. She came across Batman stunned on the floor after the large explosion in the Warden's office killed Dr. Young, making an empty remark of pity and expressing how Joker "hates a squealer". She then took the tape off of Sharp's mouth and smacked him around with his cane, accidentally breaking off the jewel tip of it after aggressively striking him on the head. She left a few goons to take Batman to 'the party', but he defeated them and used the Warden's DNA traces from his severed cane tip to follow Quinn. She then made her way to the Penitentiary with the Warden, forcing him to read a variety of threatening statements written by Joker over Arkham's intercom system and torturing him when he hesitated and insulted her.
After locating the Warden locked up in an abandoned control room, Batman saw Harley on a nearby monitor, passing Poison Ivy's cell. Despite not being on the 'party list', Poison Ivy convinced Harley to let her free. As Ivy happily strode away and blew Harley a kiss, Harley sighed and said "She's a good kid." Batman followed Harley and surpassed a variety of her traps until there were few goons left standing. Harley even electrified the pacification system on the asylum floor to the maximum power to stop his advance, electrocuting a security guard as a demonstration. Batman eventually got past this obstacle and fought his way through the remaining Blackgate convicts and escaped mental patients before the fifteen remaining thugs attacked Batman in the Extreme Incarceration cell block. After they were defeated, The Joker decided that Harley had failed him, removing Harley from the 'party list', much to her annoyance. Out of anger, Harley used her acrobatic skills to attack Batman but was defeated with ease. Batman took Harley's 'party list' and scanned her hand, acquiring her fingerprints.
Batman locked up Harley in an adjacent cell, with Harley accidentally revealing the Joker's location and claiming he would rescue her. Batman left Harley crying alone in her cell. After walking into a nearby room to examine a glowing green trophy placed there by Riddler, Batman became trapped inside after the a set of bars slid over the doorway. Harley then taunted him: "The stupid bat has fallen into my trap!", suggesting that she had Riddler place the trophy in there to trap him. Batman used his Explosive Gel to destroy the wall above the cell and climbed out back into the cell block, prompting a shocked Quinn to give a violent start and demand, "What? How did you get out of there!?"
It can be safely assumed that Quinn was escorted back to her usual cell by the surviving Arkham staff upon the Joker's final defeat.