Speaking on the PBS television network, Clooney said Mr Bush and his cabinet were behaving like Big Tony and his mobster family in the TV show.
Clooney accused the President of cutting a deal with France and Russia to ensure the UN Security Council will not complain when "we go into a war and kill a lot of innocent people".
"Are we going to try and talk to Saddam Hussein...without jumping in and killing people first?" he said.
"I don't believe we're going to wait until the last resort to do it. That's what bothers me."
Clooney is the latest celebrity to add his voice to the anti-war cry.
Last month more than 100 entertainers including Martin Sheen, Kim Basinger and Samuel L Jackson sent a letter to Mr Bush urging him not to start a war.
The UK's Poet Laureate has written an anti-war poem in which he casts doubts over the motives behind a possible war and director Martin Scorsese has also questioned America's stance.
The Gangs of New York director said many Americans were cynical about the US administration's intentions and its relationship with the oil industry.
The criticism comes amid growing opposition to a potential war.
Tens of thousands of anti-war protesters held demonstrations at several rallies across the US at the weekend.