In the four months since Joey Salvo's assassination, Simone is working odd jobs since he has been suspended by Internal Affairs pending their investigation, while he approaches Sipowicz asking about his and others incitements by the FBI who think that Salvo's death was an inside job within IAB, and Lt. Shannon from IAB tells Lt. Fancy that he may know the person who killed Salvo.

In the fourth season of this award-winning show, the action at New York City's 15th Precinct is as hectic as ever. While Lieutenant Fancy continues as precinct commander, Detective Andy Sipowicz, although still a bit rough around the edges, has mellowed with the birth of his son. Detective Bobby Simone and Detective Diane Russell take the next step in their relationship, James Martinez becomes the Squad Delegate, and Greg Meadavoy considers becoming a surrogate father. But one thing that hasn't changed is the squad's determination to make sure the bad guys get their day in court and to also attempt to maintain a touch of normalcy in their personal lives even as they investigate cases that often put them directly in the line of fire.

At the beginning of the season Sylvia becomes pregnant with Andy's child. A baby boy, Theo, is born towards the end of the season. This is contrasted with the fate that awaits Sipowicz's older son, Andy Jr., who announces that he is to join the police force. Andy is finally bonding with his estranged son when he is gunned down, which leads the elder Sipowicz to fall off the wagon. Andy Jr's murderers are killed themselves by Simone in an act of self defense. Bobby and Diane, whose relationship had been put on hold while she attended AA, resume their relationship only for Diane to begin drinking again when her abusive father beats her mother. Her father is eventually killed and her mother becomes the prime suspect. James Martinez and new detective Adrienne Lesniak begin an affair but only after Lesniak tells Medavoy that she is gay, then that she is not; Martinez later breaks up with her due to her controlling and unpleasant behavior, and Lesniak eventually leaves the squad. Medavoy himself leaves his wife, recognizing that she is holding him back but it is too late to save his relationship with Donna who leaves to take up a job with Apple.

Licalsi is found guilty of the manslaughter of Marino and his driver and is given a two year sentence. Because of his involvement with Licalsi, and the belief that he withheld evidence that could have given her a longer sentence, Kelly is transferred out of the 15th and chooses to leave the department altogether. He is replaced by Bobby Simone, a widower whose previous job was that of driver for the Police Commissioner. This does not sit well with Sipowicz but in time he learns to accept his new partner and, as his relationship with Sylvia leads down the aisle, asks Simone to be his best man. After an affair with a journalist who uses information that he gives her in an article, Simone begins a relationship with another new officer in the squad, Diane Russell. Sipowicz, still a recovering alcoholic, recognizes in Russell's behavior that she also has a problem and, after much prompting, she herself goes to AA. Elsewhere, due to his lack of self-belief that a woman like Donna could love him, Medavoy's relationship with her breaks down, due in no small part to Donna's visiting sister.

Each week viewers see the gritty reality of life in a New York City Police unit as the officers go about their work with a grim determination. Two partners, Detectives Andy Sipowicz and John Kelley (later replaced by Bobby Simone), are the central characters in this weekly police drama, and personify very different approaches to their difficult job. Sipowicz's brash gruffness (covering an emotional vulnerability) is tempered by the precise and controlled demeanor of the two partners with whom he has worked.