Ask him about his seemingly permanent bachelor status and, without skipping a beat, the 48-year-old announces: "I'm going to get married tonight... at some point."
Since he first graced our screens in ER back in 1994, Clooney's been deftly fielding questions about his latest love interest.
If you ask him a silly question, he'll give you a silly answer.
So skilled is he now at the comic backhander that even the most innocuous of questions is likely to merit a joke response.
Take, for example, his latest film offering, the intriguingly-titled The Men Who Stare At Goats, a black comedy set in Iraq, which is the second comic-take-on-war film for Clooney after 1999's Three Kings.
"I have done a couple of war satire films, Batman And Robin, obviously being the first. Just wearing a rubber suit with nipples on it is a battle," he says, barely suppressing a laugh.
Hoping for a serious response, he's asked what drew him to star in and produce the project, along with long-time friend and the film's director Grant Heslov.
"Well, I've known Grant since 1982 and he has some compromising photos of me, so I had to do it, I had no choice."
On working with Ewan McGregor in the film, he deadpans: "After the restraining order it was really quite hard to actually work with him."
His dry sense of humour is well-documented, but up close it almost seems like a defense-mechanism. Perhaps after years of reading absurd stories about himself in the media, Clooney has given up trying to be serious with the press. Apparently calculating the most absurd comment possible to out-manoeuvre the ever-hungry tabloids.
Or perhaps, we ask, he's just a natural jokester?
"That's a little personal," he says, straight face, eyebrow raised.
Joking aside, 'gorgeous George' is enjoying a lengthy spell in the UK spotlight thanks to the fact that his three latest films have all been shown at the London Film Festival, where he appeared with his current girlfriend, Italian TV presenter Elizabeth Canalis, on his arm.
The first of these films, Wes Anderson's motion-capture adaptation of Roald Dahl's Fantastic Mr Fox, sees George in the title role - with Meryl Streep as Mrs Fox.
Up In The Air, released in January, is a romantic comedy about a businessman with a penchant for expensive business trips, and The Men Who Stare At Goats does what it says on the proverbial tin.
Inspired by journalist Jon Ronson's non-fictional best-seller, the film follows a reporter (Ewan McGregor) who discovers a top-secret experimental wing of the US military - the New Earth Army - a legion of Jedi-style warriors rumoured to have psychic powers, and the ability to kill a goat just by staring at it.
Through a sequence of flashbacks, we see a younger-looking Clooney, as Lyn Cassady, with long hair and army uniform, being taught 'psychic' skills by the programme's arch-hippy founder Bill Django (Jeff Bridges).
Despite the film's stellar cast - Kevin Spacey plays Cassady's nemesis Larry Hooper - everyone just wants to talk about the goats.
"I tell you, this goat was a particularly nice goat. We spent a long time together, he wanted to go over dying around me, so we worked on that for a while," George jokes.
"The funny thing is, the goat was a great actor. He walked in and we were like, 'OK, stare at the camera' and he was like, 'Yuhh'. If I could get Ewan to do that it would help."
Growing more serious, George explains that he and Grant had been eyeing up the script for some time.
"This is a script that's been around town for a while, all of us were aware of it for a bit and it was named one of the best unmade screenplays, so we were all sort of anxious to get our hands on it and see if there was a way we could do it - and Grant had the right ideas."
The character of Cassady is, by turns, insightful and quite stupid. With his breakthrough film role in the Coen Brothers's O Brother, Where Art Thou? George is no stranger to what he glibly calls "the idiot syndrome".
"The first time I did the first scene with the Coen brothers in O Brother, I was sort of playing him dumb and they said, 'You're the smartest guy in the room' - I thought that was really good direction and it sort of made sense.
"I always find those characters are funny to me, although I must say, as wrong as Cassady seemed at times, a lot of the stuff he did actually worked, so you're never quite sure how truly or not with it this guy is."
Some of the funniest moments in the film come when Cassady refers to himself as a Jedi, something the original military unit actually called themselves.
"None of us realised when we read the script and when we'd hired Ewan, that Ewan had actually been a Jedi [in Star Wars]. It was in the script and it's actually what they called themselves," explains George.
"So we were doing this scene in the hotel room where Ewan volunteers to come to Iraq and he says, 'Who's a Jedi?' and I go, 'I am' and we just sat there and looked at each other a minute and started laughing. It was like, 'Holy s**t, we're idiots' and then we thought, 'We're going to get a lot of c**p for that' but it wasn't something we planned at all."
George was born to a beauty queen mother and news presenter father, and grew up in a small town in Kentucky. When he was 21, he moved to Los Angeles and spent a decade as a struggling actor, with roles in TV pilots that never became full series.
Then came his big break in ER.
"Look, everything we do is luck and the truth of the matter is, I ended up on a television show that was averaging 40 million people a week. Today you hear numbers in the States about American Idol getting 17 million viewers. We were averaging episodes that did close to 50 million people in a week. That's a lot, that makes you famous no matter what you do.
"So pretty quickly, all of us on that show sort of immediately became famous," George continues, gearing up into story-telling mode.
"It was a funny thing because literally the week before the show came out, we were at Smokehouse, the restaurant across the street, and Tony Edwards had a brand new baby, we were all dressed in our doctors smocks and we walked across from Warner Bros to eat.
"And Tony gave the baby half a French fry and the baby started to choke and we're all wearing our doctors outfits and nobody knows who we are and we're all actors who are like, 'Somebody do something' and all these people were like seriously, 'You guys are doctors, you do something' and we were like, 'Help him'.
"And about a week later, they figured out who we were. So it was sort of an overnight thing for us after twelve years of doing really bad television."
Fifteen years on, and with his work at the latest film festival over, George is currently in Italy - where he has a villa on Lake Como - making another movie with co-producer Grant Heslov, a hit man story called The American.
Come January, Clooney is bound to be among the names touted for awards glory, but with so many films out at the moment, does he feel like he's competing with himself?
"I have been competing with myself for years," he jokes. "A lot of the time when it seems like you're bringing out films for awards season, you're really doing it because it's actually when grown-up films come out. It's not easy to bring out a film like The Men Who Stare At Goats in the summer. It sort of gets swallowed up and it's not easy to bring it out in February necessarily, because it's sort of a dead zone time for films, so this is really about the right time for the film to come out."
As for his future projects, George is back to his joking best.
"No more farm animals and no more children, that's my new motto."
Extra time - George Clooney
He was born in Kentucky. His father was a "news man", who he says has been the most influential person in his life.
George is known for being a joker on set. During gaps in filming on The Men Who Stare At Goats, he had rubber-band fights with his co-stars Ewan McGregor and Kevin Spacey.
He is good friends with Matt Damon, his co-star in the Ocean's trilogy. When Matt recently stayed with him in his Italian villa, George took in the waistband of Matt's trousers everyday to make him think he was putting on weight.
George was briefly married to Talia Balsam in 1989 and has since been involved with a number of women, including former Las Vegas waitress Sarah Larson.