We're introduced to 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.

While John and Eva are investigating the death of a student at a private school in New York City, a big revelation is made. A flashback of 1941 reveals a big secret that John was keeping to himself and John's relationship with Omar's mother is explained.

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.

A nun is brutally raped and murdered; a fashion designer survived a similar attack. John takes charge of the case and realizes he was involved in similar circumstances in the 1800s when he worked for a wealthy landowner. Meanwhile, John and Sara begin getting to know each other.

John alongside Eva investigates the case of a homeless man who died of an 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 had to enter a 12-step program in 1964 after being drunk too many times.

When police find a bullet-ridden body in an apartment in Chinatown, John and Eva are called to investigate. The deceased young man's striking similarity to Roosevelt, a lost son of John's from the early 1900s, prompts him to take a personal stance on the case. The search for the killer leads John to the Spoors, a violent crime family headed by Roosevelt's kin. The discovery makes John question the actions of his past and the reverberating consequences they have on those around him.

Andy Gleason, John's first partner on the force, is dying of leukemia brought on by a bullet fired by an unseen shooter. He asks John to bring his killer to justice, because of his weakened condition he can't do it himself. The investigation brings John in contact with the Russian Mafia while he flashes back to how he got started as a police detective.

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 meantime, 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 when Omar points out that John is still immortal, he begins to wonder if she truly is the one. and decides to back away from their growing relationship.