John Amsterdam - a brilliant New York homicide detective who's also an immortal being. John will only start aging once he finds his true love which hasn't happened for the past 400 years of his life. John's homicide partner is a woman named Eva Marquez. The only person who knows John's secret of immortality is Omar, who also happens to have his own secret safe with John. John escapes death when he finds himself investigating the murder of a socialite who is somehow connected to his past.

John alongside Eva investigates the case of homeless man who died of overdose. The best friend of the homeless man believes it was a homicide. While searching the belongings of the dead homeless man, John gets hold of an expensive guitar in his locker. In the meanwhile, John remembers when he was an addict and entered a 12-step program in 1964 after being drunk too many times.

John and Eva investigate the suspicious death of a student at a prestigious New York City private school which leads to the revelation of a twisted "affair." One of John's biggest secrets is revealed, following a flashback to 1941.

John Amsterdam is called in to investigate the rape of an Indian supermodel, Amartya Vikram, who is reluctant to testify against her attacker. She finally does so over the objections of her conservative family, but the rapist, Phillip Long, is freed on a technicality. After Long apparently murders Amartya for revenge, John must ensure the killer is brought to justice while dealing with memories of his own past and another time he confronted a rapist.

John and Eva investigate the murder of bullet-ridden body found in Chinatown. However, the body looks similar to Amsterdam's lost son from the 1900s, Roosevelt.

A homeless Gulf War veteran confesses to the grisly murder of a controversial psychiatrist, but Amsterdam is skeptical. While reviewing the psychiatrist's soon-to-be published book, Amsterdam contemplates the reliability of memories and the reasons people bury them. Could the motive for this murder lie in the psychiatrist's own research? The murder also brings Amsterdam closer to finding "the one" who he believes will unlock his heart and make him mortal. Though he's certain the sparks he feels are real, he encounters the unexpected.

Eva investigates the case of a woman who apparently drowned, alongside John who is recovering from a gunshot wound. The death is apparently related to robberies of wealthy men linked to a dating service. In the meanwhile, John looks back at his life in the 1920s, when he committed fraud and stole an expensive diamond pendant from his lover. Also, John wants to be sure if Sara is his true love, who can convert him to a mortal. But John is unwilling to hurt her feelings by keeping secrets about his past to himself, and as a result, decides to back away from the growing relationship between the two.

Andy Gleason, John's first partner on the force, is dying of leukemia brought on by a bullet wound fired by an unseen shooter. He asks John to bring his killer to justice due to his weakened condition. The investigation brings John into contact with the Russian Mafia while he flashes back to how he got started as a police detective.