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The blast, which occurred at the city's port on Tuesday, has claimed the lives of at least 145 people and injured more than 5,000.
The cause of the explosion is yet to be determined. However, it has been linked to a fire that ignited a warehouse full of ammonium nitrate.
Countries around the world, including the UK, have pledged aid and now the celebrity couple have made their own sizeable donation.
The Clooneys, who live in Britain, have donated $100,000 (£76,000) to three Lebanon-based charities.
“We’re both deeply concerned for the people of Beirut and the devastation they’ve faced in the last few days,” the couple said in a statement.
The couple added: “We will be donating to these charities $100,000 and hope that others will help in any way they can.”
Human rights lawyer Amal, 42, was born in Beirut but she and her family left when she was just two-years-old, escaping the country’s civil war.
They eventually settled in Gerrards Cross, Buckinghamshire, and Amal later studied at Oxford University.
She became engaged to Hollywood star George in 2014 and they married later that year. They have two children, three-year-old twins Ella and Alexander.
The donation comes after the pair contributed more than $1 million (£807,000) to help those impacted by coronavirus in April.
The couple made a significant contribution to six charities and organisations around the world, including the Lebanese Food Bank.
You can read more about how to help and donate to victims of the disaster in Lebanon here.