"Meghan has climbed socially and left us behind — that's how I feel," he said.
"I think that's what happens when you're 'underclass' and trying to rise above the reality of your situation."
He went on to comment on her fractured relationship with Thomas Markle, Meghan's father, who did not attend her wedding to Prince Harry in May 2018 and has admitted to selling stories about her to UK tabloids.
"She's a prima donna because he (Thomas) treated her really well," he told the magazine.
The interview came out shortly after a royal source claimed Meghan, 38, is keenly aware she's being "pitted against" Kate Middleton.
It was also in the wake of the recently documentary filmed during the Duke and Duchess' tour of South Africa.
The parents of six-month-old baby Archie opened up to journalist Tom Bradbury about their struggle with being in the spotlight in the documentary: Harry & Meghan: An African Journey.
Meghan was close to tears as she described feeling "vulnerable" while speaking about being a new mum.
She said she was "not okay", amid continued scrutiny from the British tabloid press, which has hounded the Duchess over her relationship with her father, and speculation over rifts within palace walls.
Commenting on the feud rumours, Mike said Meghan's "immaturity" could be the reason.
"Coming from her background, she may have a chip on her shoulder," he said of Meghan.
"It could be that that's part of the problem she's having with her sister-in-law," he said. "Meghan is immature in some ways.
"I feel that because of the way she acts — not only towards family members, but other people."
Since the interview, royal fans have come out in support of Meghan, taking to social media to comment on his claims.
"Meghan, get your uncle some help please," one said.
Another said: "We all have a 'crazy uncle.' We don't have to agree to love someone," while a third weighed-in: "Meghan, what is he doing? And why? This is bizarre – if he were my virtual uncle, I'd be heartbroken by his behaviour."
Meghan's uncle Mike isn't the only family member to come out against her.
Samantha Markle, her half-sister, has called her "inhumane" and "the Duchess of Nonsense" while labelling Harry a "hamster" and a "wuss".
Meghan's father has also said he felt "hurt" by an emotional letter he was sent by the Duchess following her wedding, releasing parts of it to the The Mail on Sunday.
He later said: "I decided to release parts of the letter because of the article from Meghan's friends in People magazine.
"I have to defend myself. I only released parts of the letter because other parts were so painful. The letter didn't seem loving to me. I found it hurtful."
Thomas Markle, who lives in Rosarito, Mexico, pulled out of walking Meghan down the aisle in May last year at the last minute, after reportedly having a heart attack.
The letter Meghan sent him is now at the centre of bitter legal battle between the Duke and Duchess of Sussex and The Mail on Sunday.
