Speaking in the city where he married lawyer wife Amal three years ago, Clooney revealed that the concept for the new film, which was developed from an old Coen brothers script, came to him around the start of the US presidential campaign, when he started hearing "speeches about building fences and scapegoating minorities".
And with race, post-Charlottesville, once more in the foreground of US politics, his sixth film as a director has acquired more contemporary relevance than he and his co-writer Grant Heslov ever anticipated.
"I grew up in the South in the 1960s and 1970s at the time of the civil rights movement and we thought we were putting those issues to bed, that segregation was going away," the 56-year-old told a packed press conference.
"Of course we weren't and we still have these eruptions every couple of years that tell us we still have a lot of of work to do from our original sin of slavery and racism."
Clooney, who has a house on nearby Lake Como, is a Venice regular and "Suburbicon" is in the running for this year's Golden Lion, the top prize at the world's oldest cinema festival.
He and Amal were spotted on Thursday enjoying a no-kids date night, three months after she gave birth to their first children, twins Ella and Alexander.
The Suburbicon of the movie title is an idyllic small town suburb of neat back yards lined by wooden fences.
Packets of Tiger Tony's Frosties fill the kitchen cupboads and there is a Chevrolet or an Oldsmobile on every drive.
But this cinematically familiar territory located in an age of optimism also hosts a darker side of cruelly-enforced racial segregation and mob loansharking that provides the backdrop for the blood-splattered plot.
There is, literally, poison in the peanut butter and jelly sandwiches enjoyed by Suburbicon resident Gardner Lodge and his family.
- Lust, greed and stupidity -
Lodge, played by a deliberately beefier-than-usual Matt Damon, lives with his wheelchair-bound wife Rose, her sister Margaret and their son Nicky (Noah Jupe).
Gardner has money worries, Rose blames him for the accident that left her disabled and Margaret envies her sister's life.
But these secret tensions aside, nothing hints at the grisly mayhem which ensues after two mobsters chloroform the family during a bungled break-in, killing Rose.
Gardner's world soon begins to unravel completely in a sequence of events driven by a typically Coenesque cocktail of lust, greed and stupidity, and seen mostly through the eyes of Nicky.
Meanwhile, the Meyers, an African-American family, have moved in next door. Nicky is thrilled to have a new friend, their son Andy, to play with but the rest of the town is not so welcoming.
Andy's mother Daisy visits the local store only to discover that the price of every item has been hiked to $20, just for her.
Soon the family are under siege in their new home, hundreds of protestors banging drums around the clock in an effort to force them out.
- True story -
Clooney said he had wanted to puncture rose-tinted views of a time in American history that is frequently seen as something of a golden age of prosperity and hope.
"When you talk about 'Making America Great Again', the time when America was great, everyone assumes, was the Eisenhower 50s," Clooney said, in a reference to one of Trump's core election slogans.
"It was great probably if you were a white, straight male but other than that it was not so great. So it is fun to lift up that curtain and look under that thin veneer and see some of the real problems of our country that it has yet to completely come to terms with."
The director took inspiration from what happened when the real-life Meyers became the first black family to move into Levittown, Pennsylvania in 1957.
By the evening of their first day in their new home, they had 500 people on their lawn, Confederate flags on their house and a cross burning next door.
Clooney uses contemporary news footage of the harassment. "Sometimes you have to see the real stuff to make it really land," he said.
Through their foundation, the Clooneys recently donated $1 million to the Southern Poverty Law Center, a civil rights advocacy organization that monitors hate groups.
The gift followed clashes between white supremacists and anti-racism protestors in Charlottesville, Virginia, which left one woman dead.