Singleton, who was loosely attached to the film two years ago (12), will replace Training Day's Antoine Fuqua.
He has a deep connection to the slain rapper after directing him in 1993 Janet Jackson movie Poetic Justice.
Confirming he is onboard the as-yet untitled and castless Tupac film, Singleton says, "Tupac was the guy who I planned to do a lifetime of films with. His passing deeply affected my life as well as countless people in this world."
The film has the support of Shakur's mother Afeni Shakur and the rapper's former record label boss Suge Knight, who are among the producers.