The new 60 second ad premieres on ITV 1 on Saturday (May 8), but our readers can see a sneak preview of Clooney in action in our video player above.
It is the latest Hollywood edition of the Warburtons adverts, which have become known for their A-list celebrities. Robert De Niro and Sylvester Stallone previously starred in the ads.
In the new advert, George Clooney stars alongside Bolton bakery boss Jonathan Warburton and the actor is seen trying to get hold of him on a video call.
The ad opens in Jonathan Warburton’s Bolton office as the fifth-generation family baker eagerly awaits his 3pm break.
As the clock strikes the top of the hour, Jonathan is seen preparing his favourite snack – "the perfect slice of hot buttered toast".
We see a slow-motion sequence of toast popping up and shooting through the air, a close-up of a wave of butter quickly melting and Jonathan cutting his toast into triangles.
But the Chairman is suddenly interrupted as his receptionist runs into the room.
"Mr. Warburton, George Clooney is on the line!," she says, drawing Mr Warburton's attention to his laptop, where the Hollywood star is seen waiting.
The bakery boss, not wanting to be distracted from his toast, smiles and says “he can wait” as he closes the laptop and tucks into his toast.
Clooney is left bewildered in the final shot as he is seen staring down the laptop screen saying: “Mr. Warburton? He hung up?”
Clooney said: "It’s not every day your call is turned down for a slice of toast, but needless to say I had a lot of fun filming this spot.
"It was great working with the Warburtons team and I’m thankful for the support they are providing to the Clooney Foundation for Justice."
Warburton's said the fee paid to George Clooney for taking part in the campaign has been donated to his charitable foundation, the Clooney Foundation for Justice.
"At Warburtons, we pride ourselves on the care that goes into making sure that every single loaf is as fresh and high quality as possible.
"Quality is truly at the heart of our 145-year-old business, and this new ad is a real celebration of that passion, and we hope it will bring a smile to those watching."
The new ad will go live on social media from Friday (May 7) and will air on ITV 1 on Saturday (May 8).