The plot focuses on Grace Hanadarko (Holly Hunter), a smoking, binge drinking, and promiscuous Oklahoma City detective. In the series opener, Grace meets up with her "last-chance" angel, when after one of her drinking binges she runs down and kills a pedestrian with her Porsche. In desperation she calls out for God's help, and a scruffy, tobacco-spitting man who calls himself Earl (Leon Rippy) appears. Unfolding his wings to reveal his divine origins, Earl tells her that she's headed for hell, and asks if she's ready to turn her life over to God. When he finally disappears, the person she struck is also gone and it's as if the accident never happened. The only evidence left is a small amount of the victim's blood on her blouse, which she brings to her best friend, forensics expert Rhetta Rodriguez (Laura San Giacomo), to analyze. With Rhetta's help, Grace discovers that her accident "victim" is actually an inmate on death row, Leon Cooley (Bokeem Woodbine), who is also visited by Earl on a regular basis.

Grace is a detective investigating homicides and other major crimes for the Oklahoma City Police Department. She uses intelligence and hard tenacity to close a case. With her fellow officers, Ham Dewey (Kenny Johnson), Butch Ada (Bailey Chase), Bobby Stillwater (Gregory Cruz), and Captain Kate Perry (Lorraine Toussaint), Grace has a passion for protecting the innocent and bringing criminals to justice. She also maintains a good relationship with various street people, whom she relies on for information and favors.

Off the job Grace drinks heavily, engages in numerous one-night stands and casual encounters with men, and is having an affair with her partner, Ham. One of her hobbies is flashing her elderly neighbor, happily indulging him as he waits at his window to watch her get in and out of the shower. Grace also lies to friends and family on a regular basis to cover up her behavior. Aside from her faults, Grace is also an extraordinarily loving and generous person to those around her. In particular she loves her young nephew, Clay (Dylan Minnette]), and devotes a great deal of her time to him.

Earl appears to Grace throughout the series, hoping she'll turn away from her more self-destructive tendencies and seek God's help. Saving Grace does not promote any one religion but does use Grace's story to discuss the topic of faith, and how difficult faith can be in such an imperfect world.

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