Former Syracuse, New York, police detective Carrie Wells has hyperthymesia, a rare medical condition that gives her the ability to visually remember everything. She reluctantly joins the New York City Police Department's Queens homicide unit after her former boyfriend and partner asks for help with solving a case. The move allows her to try to find out the one thing she has been unable to remember, which is what happened the day her sister was murdered.

Major Crimes explores how the American justice system approaches the art of the deals as law enforcement officers and prosecutors work together to score a conviction. Los Angeles Police Captain Sharon Raydor heads up a special squad within the LAPD that deals with high-profile or particularly sensitive crimes.