"They're just chasing Meghan Markle everywhere, she's been pursued and vilified", Clooney said at a promotional event for his new film, according to the UK's Press Association (PA) news agency.
Thomas shared the letter with Daily Mail after friends of his daughter spoke with People about it, saying the Duchess had reached out to her father to try and heal the rift only to be asked for a photo shoot with Prince Harry.
She says: "I don't think Charles will stand for her being anything less".
Addressing the speculation, Clooney said, "Oh yes, I'll be godfather of the royals apparently", before clarifying his sarcasm and telling reporters, "No!"
In the latest episode of The Windsors, we explore how a girl from a tiny village wound up as the future King's consort, and the challenges she faced to get there.
An unnamed friend of Los Angeles-born Meghan told U.S. magazine People: 'He's never called; he's never texted.
However, this recent scandal is the one that may have possibly pushed her over the edge when it comes to her family, and a source said that she isn't planning on releasing a comment about her father leaking her private letter because she doesn't want to make things worse.
They also expressed their concerns for Meghan and her unborn baby.
They mentioned a five-page letter she wrote to her father, Thomas Markle Sr.
She later added: "He did try to contact her she was the one who ignored him and all of us".
The former Hollywood lighting director, who lives in Mexico, said that he never meant to make the handwritten letter public "out of respect for Meghan" - but says he has been forced to do so now because its contents have been falsely portrayed.
Meghan has also faced intense interest from the unsparing United Kingdom press since her engagement to Prince Harry was announced in 2017.