The video uploaded this week onto YouTube comes as President Barack Obama's administration tries to sell the agreement to the public and a sceptical Congress.
Washington and five world powers reached an accord earlier this month with Iran that reins in the Islamic republic's nuclear programme in exchange for an easing of crippling economic sanctions.
The video starts with a joke comparing nuclear war to being "toasted."
The Hollywood cast is then joined by other figures including Jordan's Queen Noor, retired US ambassador Thomas Pickering and former CIA officer Valerie Plame, to explain details of their Iran deal endorsement.
More From This Section
"Look, it is true that if Congress sabotages this deal there would be nothing stopping Iran from getting the bomb," Pickering says.
The video presents war as a likely alternative to the deal.
Plame, whose identity as a spy was leaked in 2003, engages with the comics to drive the point home.
"Once a war begins, the chances of Iran developing a nuclear weapon would only increase," she said before a joke with Black about her revealed identity.
"The agreement currently on the table is the best way to ensure Iran doesn't build a --- bomb," the Oscar-winning Freeman said, with the expletive bleeped out.