The Lonely Island comic joined the cast of the comedy sketch show in 2005. He rose in popularity with Digital Shorts including 'Lazy Sunday' and 'D**k in a Box'.
Samberg, 33, told The New York Times that he has finished his eight-year run on the show and will not be returning in the fall.
He said: "It's an incredibly emotional and strange moment in my life. Obviously it's not a huge shock, but I did officially decide not to come back."
Samberg is the second SNL cast member to leave this year.
Kristen Wiig, best known outside the show for her award-winning movie Bridesmaids, has left the programme after seven years.
"She kept saying it just feels like it's her time," Samberg said of Wiig's departure. "I connect with that. Something about it just feels like it's the moment. My contract's up and I did so much more than I ever thought I would ever even do."
Fred Armisen, another cast member who has been rumoured to be departing, recently said that he still wants to return to Saturday Night Live next season.
Watch Andy Samberg in '100th Digital Short' below: