Courtney Matthews contracted a deadly encephalitis virus while pregnant with her son. She had hoped that the man she loved, Nikolas Cassadine, had fathered her child but two separate paternity tests confirmed that her former husband Jasper Jacks (Jax) was father instead. She delivered her son prematurely and learned upon her deathbed that Jax had tampered with the paternity tests. She died with the knowledge that Nikolas was her son's father. However, Jax kept the paternity a secret and claimed Courtney's son as his own. Jax named the infant John and conspired with Carly Corinthos to keep Nikolas away from John.

In time, the child's true paternity was revealed and Nikolas Cassadine renamed his son Spencer. Nikolas came from a royal bloodline and was considered a prince, as was his new son Spencer. For the first few years of Spencer's life, Nikolas took Spencer on many trips abroad but Port Charles remained their home. As Spencer grew older, he expressed his desire to remain in town so he could court his love interest Emma Scorpio Drake. Shortly after Emma agreed to date Spencer, she ended their relationship and chose to date Spencer's cousin Cameron instead. Spencer was crushed by the rejection but vowed to win Emma back.

While Spencer bided his time with Emma, he developed a connection to his father's girlfriend Britt Westbourne. Nikolas had ended his relationship with Britt after he discovered that she had lied to him repeatedly. Spencer remained fond of Britt and hoped that she would become his mother. Together Spencer and Britt arranged for him to run away while Britt consoled Nikolas during Spencer's absence. The plan worked and Britt and Nikolas reconciled. Eventually Britt's manipulation was discovered and to Spencer's dismay, his father removed Britt from their lives.

In 2016, Spencer was considered an orphan after Nikolas was presumed killed by Valentin Cassadine.. Spencer's grandmother, Laura Collins, was his legal guardian after his father's presumed death. In November 2016, it was revealed that Nikolas and Spencer were never really the Cassadine heirs, Spencer lost his entire inheritance to his great-uncle Valentin. It was revealed through Mikkos' hidden will that he left his entire estate to the eldest living son.

In an attempt to avenge his father's "murder" and regain the fortune he had lost, Spencer filed a wrongful death lawsuit against Valentin, with Ava as the star witness because she had seen Valentin shoot Nikolas. However, Ava cut a deal with Valentin at the last moment, which infuriated Spencer. By August 2019, it was revealed that Nikolas had survived his brush with death, and there was a codicil to Mikkos' will which proved that Valentin was not the rightful Cassadine heir - Nikolas and Spencer were.,

On January 20, 2020, after more than three years of separation, Spencer was finally reunited with his father. However, after learning that Nikolas had willingly stayed away for all that time, Spencer rejected his father and declared that Nikolas was just as heartless as Valentin. To make matters worse, Nikolas and Ava had gotten married.

On May 4, Spencer sent Nikolas a letter which contained an ultimatum. Spencer promised to let Nikolas back into his life if he divorced Ava. Nikolas desperately wanted to reconnect with Spencer, but he didn't want to risk losing the Cassadine fortune. Eventually, Nikolas called Spencer to let him know the answer to his ultimatum.

On August 13, it was revealed that Spencer forgave Nikolas and that the two were conspiring to make Ava feel so guilty that she would divorce Nikolas without taking the Cassadine fortune. Their scheme backfired when Ava overheard Lulu Spencer spilling the news of Nikolas' scheme to Dustin Phillips.

On February 19, 2021, Ava received an encased roach as a Valentine's Day gift while at the Port Charles Grill with Nikolas. Nikolas claimed it was not the present he got for her. On February 22, Ava received Nikolas' gift, a bracelet, and she asked the waiter who brought other gift. The waiter later told her that the gift had already been there when his manager came to work, along with a note addressed to "Mrs. Cassadine". Ava immediately suspected Ryan Chamberlain and called police commissioner Jordan Ashford. Jordan said she had not gotten a call about Ryan Chamberlain and that he should still be paralyzed in the facility he was sent to.

On April 6, Ava received a prosthetic hand with a note that pointed to Ryan as the sender.

On June 8, a photo of Nikolas and Ava was found stuck on a door at Wyndemere with a knife through it. Nikolas recognized the knife as one of his own. A note on the back of the photo threatened Nikolas and Ava by mentioning nurse Mary Pat Ingles' head being cut off.

On June 21, Avery found a stuffed bear inside Nikolas' Metro Court suite that had Ryan's voice saying, "I can't wait to be a family." Dante took the bear as evidence.

On July 1, Spencer broke into the Jerome Gallery while wearing a mask. Nikolas had an alert that told him about the break-in. Trina later ran into Nikolas in the gallery and pepper sprayed him in the face. Trina apologized once she recognized Nikolas. Later, Spencer sneaked around the gallery and bumped into Trina, who tried to spray Spencer but the pepper spray is empty. She instead threw a remote at his head to set off Spencer's trap.

Spencer attended Trina's graduation party at The Savoy, having entered the back way and scaring Trina. They talked and flirted, with Spencer having complimented Trina having calling her "badass." Spencer claimed his name was Victor and that he was a barback at the nightclub. When he is alone, Spencer looks at a picture of Laura, Nikolas, and himself. He called Nikolas "father," which confirmed that "Victor" was none other than Spencer.

Later, Trina ran into Spencer, whom she still thought was "Victor." Spencer had been wearing only shorts while sunbathing on Pier 54. Trina had been searching for a place to watch the fireworks. Spencer assumed Trina had been searching for him, and he suggested they wear their birthday suits. Trina offered to take Spencer to the park instead.

At the park, Trina wanted to introduce "Victor" to Cameron and Josslyn. Spencer claimed he was thirsty and left to grab some bottles of water, but he disappeared. Cameron told Trina that she may not want to be friends with someone who was playing games. Trina left to watch the fireworks with her mom, Dr. Portia Robinson, while Spencer spied on her from the bushes.

Spencer later apologized to Trina for not having shown up, and he gives her a bottle of water. The two talked about art, and Spencer said that he lived in a studio in an expensive part of town. He added that his mother had died and that he had been in Europe. Portia appeared, and Spencer turned down an offer to have dinner with the Robinsons. Later, Spencer visited Mike Corbin's grave.

On March 25, 2022, after having been released from Spring Ridge and fresh from a fight with Esme after having seen Esme's pregnancy test kit, Spencer confided in Cameron that he and Esme had broken up. Spencer feared that Esme might be pregnant with his child, and he said he didn't want to be stuck with Esme the rest of his life. Luckily for Spencer, the pregnancy scare was a false alarm, but Spencer used the opportunity to try to turn the tables on Esme because Spencer had started to suspect Esme of recording an intimate moment between Cameron and Josslyn, posting the revenge porn on the Internet, and framing Trina for the crime.

During Trina's trial, Spencer provided Trina with an alibis, but it cost him dearly. He was forced to admit that on the day the revenge porn was posted, he had slipped out of Spring Ridge to visit his mother's grave on the anniversary of her death. During the graveside visit, Spencer had run into Trina. Eventually, Trina was cleared of wrongdoing when the bartender who had sold Esme the phone used for the revenge porn testified in court about the sale of the burner phone and Esme's attempt to silence him by poisoning him.

In October 2022, Spencer was sent to Pentonville to serve three months for escaping from Spring Ridge. During his incarceration, Spencer was harassed by a prisoner named "Book" who was angry that Spencer had been assigned to work in the prison's library. "Book" had hoped to be the prison's librarian. "Book" harassed Spencer, made certain Spencer had ill-fitting prison clothes, and "Book" withheld Spencer's bedding. Spencer's great-uncle Cyrus Renault - who was also serving time at Pentonville - interceded on Spencer's behalf, but Spencer was leery accepting any help from his notorious great-uncle.