The 57-year-old actor - who was among the guests when the former actress, who was then known as Meghan Markle, married Prince Harry last May - has warned history could "repeat itself" if the ex-'Suits' star continues to be "pursued and vilified" in the same way the prince's late mother, Princess Diana, was until her death in a Paris vehicle crash in 1997.
The actor, who is a friend of the British royal and her husband Prince Harry and attended their royal wedding with his wife Amal last May (18), gave the warning after United Kingdom tabloid the Mail on Sunday published a letter Meghan reportedly wrote to her estranged father, Thomas Markle.
Clooney told reporters at a Television Critics Association conference in Pasadena, California that Meghan is "a woman who is seven months pregnant and she has been pursued and vilified and chased in the same way that Diana was and it's history repeating itself".
He continued, "We've seen how that ends".
"They're just chasing Meghan Markle everywhere, she's been pursued and vilified", Clooney told Australian magazine WHO.More news: Secretary Pompeo kicks-off five nation trip in Central Europe
More news: Ex-boyfriend charged in death of woman in suitcase
More news: British Defence Minister warns Russian Federation about high price for provocations
In the note, sent in August, Meghan addressed her father as "Daddy" before accusing him of breaking her heart "into a million pieces" by allegedly lying in the press and publicly attacking her husband Prince Harry.
Reacting to the family row Clooney said Meghan's treatment was "irresponsible" and that she was getting a "raw deal".
There's still a long way to go before the Duke and Duchess of Sussex's baby starts talking, but when he or she does, we know what they'll be calling grandad Prince Charles. "I'm sort of surprised by that".
She later added, "I doubt #GeorgeClooney would ghost his mother for no legitimate reason".