The former ER star, who personally flew the Duke and Duchess of Sussex out to he and Amal's Lake Como home last summer, said: "They're just chasing Meghan Markle everywhere, she's been pursued and vilified", the father of two told reporters, according to Who magazine.
As per one of the U.S. mags, her friends said that she wrote the letter to heal the differences Meghan and her father had since a year ago May.
Clooney, who is friends with Meghan and her husband Prince Harry, defended the Duchess after Britain's Mail on Sunday newspaper published a personal letter allegedly sent by Meghan to her estranged father.
"Oh yes, I'll be the godfather of the royals apparently", he said before laughing and confirming, "No!" But she's eight months pregnant, and vilified and persecuted her as Diana.
"And we've seen how that ends".
Meghan has also faced intense interest from the unsparing United Kingdom press since her engagement to Prince Harry was announced in 2017.
Meghan Markle's father Thomas Markle has spoken to the press many times.
And Meghan's gleaming appearance tonight, just months before she is due to give birth, shows she is refusing to let the row get to her.
Meghan said that he did not call to tell her that he could not make it to the wedding and that he was spreading lies in saying that she had not helped him financially.
As Mr Markle threatens to release more content of the five page letter, The Daily Telegraph have reported that palace aides are taking legal advice before Meghan decides whether she wants to take formal action.
Meghan and Prince Harry announced last October they are expecting their first child in Spring 2019.
In the letter, she reiterated that she begged him to stop reading tabloids and said the lies in the press came from half-sister Samantha Markle.
In it, Markle criticized her father for giving interviews to the tabloid press and fabricating stories. "I defend millions of women globally, why wouldn't I do the same for her".