In 1987, Sean was put on a hit list, made by a group of terrorists that were targeting spies. Due to his occupation as former head of the WSB, Sean was next up on their hit list and his good friend Robert, returned to Port Charles to help protect him, his family and friends. With the help of Anna, Tiffany Hill, and Duke Lavery, Robert and Sean traveled with them to Mt. Rushmore and the group was able to stop and catch the rogue terrorist group and their leader.
In 1988 Sean started to suffer from a mid-life crisis. During this time he fell for Dr. Greta Ingstrom, but her husband resurface, so Sean went back to his past love Tiffany, who was unhappy with his wandering ways. Sean and Tiffany were able to work out their differences and the two were married in the Quartermaine mansion amongst friends and family. After the wedding, Sean assists his friend Felicia Jones in tracking down her husband Frisco's grave after she was informed that he had been killed.
Sean's insidious past came back to bite him in the form of his arch-nemesis Cesar Faison who arrived in Port Charles in 1990. Through flashbacks, it was revealed that the two had plotted to destroy Robert and Anna's marriage back in their WSB days. Back when Sean was head of the WSB, he successfully worked with rival spy agency leader Cesar Faison to break the Scorpios apart. This was because Sean feared he was going to lose his two best agents to a life of wedded bliss outside the agency.
Robert and Anna found out the truth, but nevertheless, Sean still helped his friends defeat Faison, before he could force Anna into marrying him. Cesar took his revenge on Sean in 1991, when he poisoned Sean's wife Tiffany with a mysterious illness that left her comatose. Cesar held the only cure and used this as leverage to made Sean do his bidding, though at the time Sean didn't realize that Cesar was behind Tiffany's illness. When Sean found out that Cesar was behind everything, he once again teamed up with Robert and Anna to bring him down.
In 1992, Sean agreed to serve as acting Police Commissioner while Robert left to pursue Faison, and assumed the position of permanent PCPD Commissioner when Robert and Anna are presumed dead from a boat explosion that occurred when they were trying to stop Faison. Sean split his time between comforting his grieving goddaughter Robin, and dealing with his nemesis Luke, who arrived back in town in 1993 and gave Sean nothing but grief. On the personal front, his marriage began to fall apart, when his wife Tiffany became obsessed with adopting her deceased sister Cheryl's son Lucas. Unfortunately, Cheryl's will left custody of Lucas to Bobbie Spencer and Dr. Tony Jones.
As their marriage fell apart over the adoption dilemma, Sean began an affair with lawyer Jessica Holmes. In the meantime, Tiffany is thrilled when she discovers that she is pregnant, but is crushed just as quickly when she overhears Jessica tell Sean that she is pregnant as well. Sadly, Tiffany miscarries her child and at the same time, Jessica admits to Sean that she had lied and wasn't really pregnant. Sean and Tiffany start to work on recoiling their marriage, just as Jessica learns that she really is pregnant. Jessica threatens to tell Tiffany and Sean threatens her in response, warning her to keep her mouth shut. Jessica is later found dead and Sean thinking that Tiffany committed the crime, confessed to the murder. However it was later proven that the insane Ryan Chamberlain was the real murderer and Sean and Tiffany were in the clear.
In 1994, Sean and Luke are caught in a shoot out with mobster Frank Smith and Sean is shot by Frank. Luke kills Frank before Frank finishes him off. Later that year in Port Charles Sean is accidently shot by Luke because of Joe Scully a former mentor to Sonny. Before Sean is sent off to heal and recuperate an overjoyed Tiffany announces to their friends and family that she is pregnant. When GH recommends that they transfer him to another treatment facility in Boston, Massachusetts, Sean and Tiffany decide to leave town to get Sean the best care possible and start a new life with their child.
Sean and Tiffany returned to Port Charles in 2008 on Night Shift to help their friend Robert, who was battling colon cancer. While in town, they shared with their friends that they now had a teenage daughter, named Anna Donely and that she was named after Anna Devane.
In May 2021 Sean Donely passed away off-screen from dementia, thus dissolving their marriage. Sean's actor, John Reilly, passed away in real life in January 2021.