"I just have such respect for the queen. I don't think this should be happening to her," the president told Fox News.
He's pro-Brexit, but President Donald Trump is anti-Megsit.
Trump then sang the praises of Queen Elizabeth II, who was reportedly "hurt" by the couple's stunning surprise announcement.
"She's a great woman. She's never made a mistake, if you look. She's had like a flawless time," Trump said.
Asked if her grandson Harry should return to the royal fold, Trump said, "I don't want to go into the whole thing. I just have such respect for the queen. I don't think this should be happening to her."
While Trump has praised the queen in the past, he's also been critical of the Duchess.
During an interview with a British paper last year, Trump called Meghan "nasty" because of comments she'd made about him during the 2016 election. The then-Meghan Markle had called Trump "misogynistic" and "divisive."
"She said she would move to Canada if you got elected. It turned out she moved to Britain," the interviewer told Trump during a visit to the United Kingdom last June.
"There are a lot of people moving here. So, what can I say? No, I didn't know that she was nasty," Trump said.
Asked if it was "good" that there was now an American in the royal family, Trump said, "I think it's nice, and I'm sure she'll do excellently." "She'll be very good," he said.
Meghan was on maternity leave during Trump's visit, and did not attend the state banquet in his honor at Buckingham Palace.