"I've had so many extraordinary moments in Venice. This festival is without question my favourite, and to be given the Golden Lion is a tremendous honour. It also probably means I'm old, but I'll take it," the 65-year-old US actor said in a statement.
The 83rd Venice Film Festival, regarded as the most prestigious after Cannes, runs from September 2 to 12.
Clooney became known in the hospital series ER in the 1990s. His best-known films include Ocean's Eleven, Syriana, for which he received the 2006 Oscar for best supporting actor, Michael Clayton, Up in the Air, The Descendants and Gravity.
In 2025 Clooney presented Jay Kelly directed by Noah Baumbach in Venice, but fell ill during the festival and had to cancel his appearance at the press conference.
Festival artistic director Alberto Barbera paid tribute to Clooney in his triple capacity as actor, director and producer.
"He is endowed with the gift of making his characters seem not only credible but desirable, approachable, and human, thanks to his undeniable charm," Barbera said.
"But Clooney's charisma is constructed on his credibility, not on his image, because his seductive side has never been merely aesthetic," he added.