He has been in more than 400 episodes of the police drama, earning a SAG Award and Emmy and Golden Globe nominations for the role.
"The time has come for me to move on and take Jack McCoy with me," Waterston said in a statement on Friday.
"There's sadness in leaving, but I'm just too curious about what's next. An actor doesn't want to let himself get too comfortable."
Tony Goldwyn, who starred in Scandal and the 1990 film Ghost, has been cast as the new district attorney.
McCoy and the prosecutors would take up the legal case once the New York City detectives were finished investigating a crime, representing, as the narrator says, "two separate yet equally important groups".
McCoy was a brilliant, hard-charging, angel of justice, prone to bouts of moral outrage and slicing right to the truth.
"Your grief might seem a little more real had you not just admitted you cut off your wife's head," he once told a defendant.
Bushy-browed Waterston began his acting career as a stage actor in New York with a number of Shakespeare roles, including Lear, Hamlet, Polonius, Laertes, Prospero, Leonato, Prince Hal, Silvius, Cloten and Benedict.
That led to Waterston playing Nick Carraway in The Great Gatsby opposite Robert Redford, and the role of Tom Wingfield in a television production of Tennessee Williams' The Glass Menagerie, starring Katharine Hepburn, for which he got his first Emmy nod.
Waterston, 83, joined Law & Order in season four in 1994 and stayed until the show stopped in 2010, returning for the reboot in 2022.
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