It has not yet been announced which clubs the Vunipolas will be joining or whether they are heading abroad.
They follow England team-mate Owen Farrell in departing the StoneX Stadium in the summer, with the fly-half moving to French side Racing 92.
All three could make their final appearances for Sarries in the Premiership final at Twickenham on 8 June, after the club made the play-offs by beating Bristol on Saturday.
“To watch Billy develop into a world-class number eight and a thoughtful, supportive team-mate has been a privilege for us all,” Saracens director of rugby Mark McCall said.
“He has contributed enormously to the progress we have made as a club.
“On the field his intuition and amazing skill set, combined with his competitive spirit and physical attributes, made him a force to be reckoned with.
“Off the field, Billy was sensitive to the needs of the group and a fantastic mentor to many younger players.
“Mako’s all-around skill set, rugby intelligence and physicality made us – as coaches – rethink what’s possible from a loose-head prop.
“Mako has achieved a phenomenal amount in the game; three Lions tours, multiple England caps and being central to all Saracens has created.”
McCall added: “Manu has given his heart and soul to this club and we have loved watching him develop from boy to man.”