"It's gonna work out and there is gonna be a new country formed. That is a pretty amazing thing," Clooney said in an interview in south Sudan's capital Juba.
The actor and human rights activist arrived in Juba on Thursday in a show of support for the impoverished region still recovering from decades of war, after launching a Google-powered mapping project aimed at preventing abuses in Sudan.
His "Satellite Sentinel Project" is designed to combine satellite imagery and field reports to monitor Sudan's volatile border region during the referendum.
Some 3.9 million southerners have registered to vote in the referendum, which is a key plank of the 2005 peace agreement (CPA) that ended a 22-year north-south civil war in which around two million people were killed.
The accord also stipulated that the disputed Abyei border region should choose simultaneously on whether to remain a part of the north or join a potentially independent south.
But that vote has been postponed indefinitely, with neither side able to agree on who should be eligible to vote.
In Abyei "you have two tribes, the Misseriya and Ngok Dinka, inside fighting... If that sparks and one of these two troops (from the north or south) move in, breaking the CPA agreement, then you got yourself a north-south war," Clooney said.
"So that is why we are sort of the skunk in the room," added the 49-year-old, who has also been involved in raising awareness of the situation in Darfur, Sudan's war-torn western region.
Asked whether he would like to punch or talk to Sudan's President Omar al-Bashir, indicted for genocide in Darfur by the International Criminal Court, Clooney said he would bring him to his house and invite some members of the ICC over for dinner.
"Will see how that goes," he said. "I would like him to come out of his protected cocoon."
The actor said people who criticised him for his humanitarian work should just stand aside.
"If they don't like what we are trying to do, then get out of the way, I don't care," he said.
"We try to save some people's lives. If we succeed then good, if we did not we tried. I don't see a downside to that."
Challenged on why so few movies are made about Africa, the Academy Award-winner said it was very difficult to find a good script on such thorny subjects as Darfur.
"Unless you are making a big spectacular 200-million-dollar 3D space film, if you are not into that then every movie is difficult to get made and it requires a good script," he said.
"We get scripts all the time about issues in Darfur, issues in Sudan, but they have to be good scripts so that you can make it.
"I know it sounds like a joke, but they are really hard to find," Clooney added.
Preparations for Sunday's referendum have been praised by visiting diplomats amid pledges by the leaders of north and south Sudan to cooperate.
But the celebrations in the south, which is widely expected to choose independence, were marred by deadly clashes on Saturday between the southern army and renegade militiamen in remote Unity state on the north-south border.
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