"She's 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 added.
Britain's famously aggressive press at first welcomed Markle into the royal fold when she and Harry tied the knot at a lavish Windsor Castle wedding last May, in a ceremony attended by Clooney and his human rights lawyer wife Amal.
The mixed-race actress was credited with breathing fresh life into a monarchy sometimes labelled stale and out of touch.
But coverage has turned increasingly critical -- despite the impending birth of the couple's first child -- with reports of palace sniping over her manner.
Tabloid newspapers have also luxuriated in stories about Markle's fractured American family.
Last week one paper published a highly personal letter they said was written by Markle to her estranged father in which she begged him to "stop lying....stop exploiting my relationship with my husband".
Clooney, who was promoting his new TV series "Catch-22", slammed the invasion of her privacy.
"I can't tell you how frustrating that is, just seeing them broadcast a letter from a daughter to a father, she's getting a raw deal there and I think it's irresponsible and I'm surprised by that," he said.
Harry recently revealed that for a long time he struggled to cope with her death, and sought professional help a few years ago.
(This story has not been edited by Business Standard staff and is auto-generated from a syndicated feed.)