Plum Island is a fictional novel about a convalescing New York Police homicide detective named John Corey, who gets involved in a multiple murder investigation while he is supposed to be recovering from serious wounds. John is originally working as a consultant for the small township, where an old friend of his is the Chief of Police, but when he is relieved of this position, he continues the investigation on his own. Eventually the county detective assigned to solve the case, Beth Penrose, invites him to collaborate with her and the team solves the original double murder, and all of the murders committed by the same man, Frederic Tobin.

John Corey is relaxing on his Uncle Harry's deck when Sylvester Maxwell, Chief of the local police, asks John to accompany him to the murder scene. Tom and Judy Gordon, biologists at the nearby Plum Island biological animal research center, and recent friends of John, have both been shot in the head on the deck of their home. John meets Detective Beth Penrose of the Suffolk County Sheriff's Office, Foster of the FBI, and a man named Ted Nash who says he is from the Department of Agriculture but turns out to be a CIA agent.

The initial investigation focuses on the Gordons stealing a virus from the Plum Island facility and selling it to a foreign government. To this end, the team of Nash, Foster, John, Beth and Max are taken on a lengthy tour of the facility, including the uninhabited part of the island that contains a revolutionary war era abandoned fort. While on the tour, John and the team meet the head of security, Paul Stevens. They also learn that the Gordons were involved in researching a vaccine for Ebola, were amateur archeologists, and had free reign to bring their boat to and from work every day, fish and swim off the beaches of the secure island, and were well liked by the entire staff. When the team meets with the director of the lab, Dr. Zollner, he suggests that the Gordons stole a vaccine, not a virus or bacteria, and that becomes the official line of the lab, the FBI and the CIA.

Max tells John he is no longer needed as an investigator, but Beth continues to consult him. John begins interviewing other people who knew the Gordons, including their neighbors the Murphys, Frederic Tobin, and Emma. Tobin and John develop an adversarial relationship, and Emma becomes John's lover.

When Emma tells John about her historical knowledge concerning Captain Kidd and the buried treasure, John realizes the Gordons were not involved in vaccines or viruses, or even drugs, but actually with the treasure. He is convinced that with Tobin's assistance, the Gordons had found the treasure on Plum Island and were going to move it to the land they had recently purchased near the water.

Tobin realizes John is approaching the solution to the murder. John does not realize how desperate Tobin is until the morning when Beth comes to John's house and advises him that Emma is dead, as are the people who found the Gordons, the Murphys.

The hurricane is breaking over the island, but John is relentless in his search for Tobin. Beth is with him and is constantly trying to get him under control, but John uses his jeep and an ax to break into Tobin's office. He discovers a map made to look ancient that shows the treasure located on Tobin's own personal land. This convinces John that Tobin killed the Gordons and never intended to keep them as partners. Tobin was using the Gordons for access to Plum Island and nothing else.

As the hurricane rages, John and Beth go to Tobin's house, only to find they have missed him by a few minutes and he has taken his big cabin cruiser boat, a smaller boat in tow, a couple of rifles and shovels and gone out to sea.

John heads to the boathouse and gets the power boat that his left started up. Beth joins him at the last minute and the two battle the seas to chase Tobin. With the weather and their lack of boating knowledge, John and Beth are soon soaked, lost and taking on water. Tobin has used his radar and circled around behind them, intent on colliding with their boat with his larger one. As he gets close to them he is also firing his rifles, intending to kill them that way.

John and Beth manage to maneuver their sinking craft that is also almost out of gas to a crash landing on the beach of Plum Island. They find where Tobin has landed, and Beth thinks the best move is to wait there. John disagrees, feeling that he needs to hunt down and kill Tobin, wreaking his own justice for the murders of the innocents and his friends. John sets off, finds two more dead bodies at the fire station, and continues his search for Tobin. He finds Tobin in an artillery bunker and the two men fight. In the course of the fight, John discovers that Tobin does not have the treasure, and believes the Gordons told John where it was. John overtakes Tobin, cuts him open and leaves him for dead. As John leaves the bunker, he encounters Stevens, who has a rifle. Stevens says he has the treasure, and the last laugh. Just as Stevens is about to shoot John, Beth shoots Stevens and kills him.

The next morning, when the hurricane has passed, John and Beth take Tobin's boat to the ferry dock and Max meets them there. John heads for Manhattan to face the wrath of his NYPD supervisor. At his home, he finds a letter from the Gordons, written before their murder, verifying everything he has now discovered. John goes to meet with his supervisors and negotiate a way out of the trouble he is in for disobeying orders.

The last chapter shows John teaching homicide investigation, as a retired police officer. It is several months after the Plum Island incident, and he misses the police force, but accepts what needed to happen. He is also unattached. John is surprised to se that Beth Penrose has enrolled in his class. She catches him up on the latest from Suffolk County, and is gently offering to be in his life again. While he initially resists, he announces to the class that he is taking her for drinks that night.