Don Cheadle has since become one of the biggest Hollywood names in activism and philanthropy, and has been involved in causes ranging from the genocide in Darfur to the more current Black Lives Matter movement. He is one of the biggest supporters and financiers of the Enough Project, a charity dedicated to countering genocide and crimes against humanity in Africa's most war-torn regions, via Enough Project. The organization has named Cheadle an "upstander." Cheadle has even co-written a book with the founding director of the organization, John Prendergast, titled Not on Our Watch: The Mission to End Genocide in Darfur and Beyond, which is a New York Times bestseller, along with the follow-up book The Enough Moment.

In 2016, Cheadle, along with George Clooney and Prendergast, presented an investigative report on the subject at a press conference at the National Press Club in Washington DC. They met with President Barack Obama, Vice President Joe Biden, Secretary of State John Kerry, Secretary of the Treasury Jacob Lew, and National Security Adviser Susan Rice. 

In the summer of 2020, he talked to NBC about the racial strife in the wake of brutal police killings and of the then-impending presidential election, saying, "From the ashes of this conflict can come great change, but it's not going to happen if we rest," he said. "It's not going to happen if we don't get behind the people that have been doing the work thus far."