On August 16, 2021, Esme Prince appeared in Port Charles. Her first stop was General Hospital, where she posed as a nurse and eavesdropped on a conversation between Ava Jerome and Laura and Kevin Collins. Ava had been the victim of a stalker who had been sending ominous messages for months. As Ava entered the hospital's parking garage, she was horrified to see that her car had been set on fire. Adding to the nightmare was the discovery near the crime scene of a hospital ID badge that had belonged to Ava's murdered daughter.

Days later, Esme arrived at Wyndemere and introduced herself to Trina Robinson as Spencer Cassadine's girlfriend. Esme took an immediate dislike to Trina because Esme had picked up on Spencer's attraction to Trina. Esme and Spencer (whom she called "Spence") had met at boarding school in France, and it quickly became clear that they had been working together to terrorize Ava in an effort to drive Ava and Nikolas Cassadine apart. When Spencer learned that Esme had torched Ava's car and planted Kiki Jerome's ID badge, he warned Esme that she had gone too far. Esme was unapologetic because the fire had been an effort to throw suspicion off Spencer as the true stalker. Unbeknownst to Spencer, Esme had another reason for being in Port Charles. Esme's biological father was the infamous serial killer, Ryan Chamberlain. Ryan had been housed at a minimum security prison named Spring Ridge because it was believed that Ryan suffered from locked-in syndrome. It was a ruse, and Esme was the only person besides Ryan who knew that Ryan had faked the syndrome to bide his time, while he and Esme formulated an escape plan that would allow Ryan to snatch Ava and disappear with both Ava and Esme. Ryan had been obsessed with Ava for years, and he was determined to reunite with her, even though Ava despised Ryan because he had murdered Kiki.

Unfortunately for Esme, her days as Spencer's pampered girlfriend hit a snag when Spencer and Esme's stalking was exposed. To spare Esme from criminal charges and possible jail time, Spencer took full responsibility for everything. Spencer and Esme moved in with his grandmother Laura Collins until Spencer's sentencing. Spencer was able to avoid going to Pentonville when his uncle Victor arranged for Spencer to serve his time at Spring Ridge. In the meantime, Esme had signed up to audit a psychology class at Port Charles University, so she could take a job at Spring Ridge. She claimed it was to be close to Spencer, but in reality Esme used the job as a cover to sneak visits with her father. The unauthorized visits ended when Kevin got wind of what Esme had been doing.

Little was known about Esme. She had been adopted by a wealthy couple with several children, but her adoptive parents were killed, and Esme had been estranged from her siblings. Esme had received a considerable inheritance, but it had been put into a trust and her access to the money had been restricted. Esme talked little about her parents, but she'd had a close relationship with her nanny Maggie Fitzgerald until Esme had been shipped off to boarding school. Esme had difficulty forming friendships, and she looked down on those who weren't a part of the upper echelon of society.

As Spencer and Trina grew closer, Esme became increasingly jealous, so she hatched a plan for a weekend ski trip with Spencer, Trina, and their friends Cameron Webber and Josslyn Jacks. Esme claimed it was to give Spencer a great sendoff before he went to Spring Ridge for a few months to serve his sentence. However, Esme knew the trip would be an opportunity for Josslyn and Cameron to be intimate, and Esme decided to exploit the situation. Esme drugged Trina's drink, humiliated Trina during a drinking game, and Esme instigated an argument with Josslyn that resulted in Spencer and Esme leaving the cabin. Before Esme left, she set up a burner phone in Josslyn's bedroom to record Cameron and Josslyn's first intimate encounter.

After everyone left the cabin, Esme returned to retrieve the phone. A few days later, Esme posted the intimate moment between Josslyn and Cameron on the Internet, and she framed Trina for the deed by dropping the burner phone in Trina's bag. After Trina was arrested and charged with posting revenge porn, Esme was pleased because she had gotten rid of a rival, and she had paid back Josslyn for rejecting Esme's overtures of friendship. Josslyn was Trina's best friend, and Josslyn had never hidden her dislike for Esme.

When Spencer was released from prison, Esme realized that he'd grown distant. Fearing that she might lose him, Esme claimed that she might be pregnant. Spencer was determined to do the right thing, so he moved with Esme back into Wyndemere. However, before taking the next step, Spencer demanded a pregnancy test. It was negative. Esme pretended to be relieved, but Spencer had finally seen Esme's true colors, and he began to secretly work against her because he was also certain that she had framed Trina. Esme redoubled her efforts to do her father's bidding by driving Nikolas and Ava apart.

Esme began to shower Nikolas with praise and support. Ava was furious that Esme had moved back to Wyndemere, so Ava moved out and refused to return until Nikolas had evicted Esme. Nikolas fell under Esme's spell, and the two had sex. Moments afterwards, Ava returned to Wyndemere and announced that she wanted to save her marriage. Nikolas made it clear to Esme that their tryst has been an isolated incident because he loved his wife. Esme didn't have any romantic feelings for Nikolas, but she demanded that Nikolas have her reinstated at Spring Ridge or she would tell Ava about Nikolas' infidelity.

Esme's troubles were far from behind her. As Trina's trial kicked into high gear, Josslyn and Trina worked together to prove that Esme had bought the burner phone used at the cabin. Curtis Ashford had also launched an investigation because he was living with Trina's mother, and he was certain of Trina's innocence. Fearing that someone would persuade the bartender into naming her as the person who bought the burner phone, Esme paid Oz Haggerty a visit, and drugged his drink. Esme was forced to make a quick escape when Curtis knocked on Oz's door.

Oz lingered in a coma, but Esme found herself being questioned by Spencer when he snooped in her room and found a batch of letters that Esme had saved from her beloved nanny. Esme had claimed that she had lost touch with Maggie, but the letters proved that Esme had lied. Esme turned on the tears and weaved an excuse that appeared to satisfy Spencer. However, Esme's luck ran out when Oz woke up from his coma. Oz testified at Trina's trial that he had sold the burner phone to Esme, and that Esme had tried to kill him by drugging his drink.

Esme decided it was time for her to leave town, but Ava intercepted her at Wyndemere. Nikolas had confessed his infidelity to Ava, and a furious Ava had decided to confront Esme. The two women exchanged heated words, and things escalated when they ended up on the parapet. During the altercation, Ava shoved Esme away from her, and Esme stumbled backwards. Nikolas appeared on the parapet in time to see Esme disappear over the ledge. Nikolas searched for Esme, but she had vanished. Nikolas and Ava presumed Esme had been killed, so they covered up the incident and went on with their lives.

In the fall of 2022, Esme resurfaced as a hook-wielding killer terrorized Port Charles by targeting people close to Trina. After Oz was felled by the killer on the piers, Esme helped herself to the money in his wallet. Afterwards, she made her way to Spoon Island. She attempted to break into Nikolas' safe when he walked in on her. Stunned, Nikolas accused Esme of being the hook-wielding killer, but Esme denied it. Esme revealed that she had barely survived her fall from the parapet, but a fisherman had scooped her out of the water and had taken her to Canada where she recuperated in a hostel.

Esme threatened to file charges against Ava, but Nikolas warned Esme that Esme was wanted by the police for drugging Oz and for framing Trina. Esme advised Nikolas to hire the best attorney that money could buy to defend her because she was pregnant with Nikolas' child. When Nikolas realized it was true, he agreed to help by giving Esme a place to hide out. Esme followed Nikolas to the north tower, but she realized her mistake when Nikolas turned the tables on her and locked her in a suite of rooms.

Esme remained Nikolas' prisoner until she managed to escape by tying bedsheets together and throwing them over the balcony. Esme made it as far as the piers where she encountered Elizabeth Webber. Elizabeth immediately pulled out her phone and called 9-1-1, but Esme lunged for the phone. Elizabeth fell backwards and hit her head. Moments later, Nikolas caught up with Esme. After checking on Elizabeth, Nikolas returned Esme to the tower. He was more certain than ever that Esme was the hook-wielding killer because Nikolas had tangled with the killer shortly after Esme had escaped.

The next day, Elizabeth turned up on Nikolas' doorstep demanding to know where Esme was. Reluctantly, Nikolas admitted that Esme a prisoner in the north tower. When Elizabeth saw Esme, she was stunned to realize that Esme was pregnant. Nikolas insisted Esme was the killer stalking Port Charles, but he promised to keep Esme confined to the suite of rooms until the baby was born. Nikolas implored Elizabeth to keep his secret, but Elizabeth left without making any promises.