Obama promptly apologized for her strong language.
The 54-year-old, who was thrust into the public eye during her husband Barack Obama's presidency, said she understands the pressure Meghan may be feeling since entering the royal family and that it's best to take things slowly.
"That whole, 'so you can have it all.' Nope, not at the same time", she said to the audience.
"It's not always enough to lean in because that s*** doesn't always work".
Mrs Obama added that her husband had always had a great affection for the Queen, saying: "Barack is so incredibly fond of Her Majesty and I won't go into his fangirling but I think it's because she does remind him of his grandmother Toot, she's smart and amusing and honest".
"And so the Queen says "just get in, sit wherever" and she's telling you one thing and you're remembering protocol and she says "Oh it's all rubbish, just get in". She rephrased her assessment. Sometimes that stuff doesn't work.
"So oftentimes it's not equal".
The first African-American first lady discussed the importance of making elite universities feel attainable to young, working class girls from Black Asian Minority Ethnic (BAME) background.
"They have to do the work to reach out to kids when they're very young", she said.More news: Ballon d'Or 2018: Top 5 leaked award winners
The crowd applauded when the word dropped while Obama laughed it off.
Mr Obama served two terms in the White House.
Speaking after the event, Winnie, who had been on stage interviewing Mrs Obama, told the Gazette: "I was so nervous beforehand but speaking to her just made us feel so comfortable". "Finally", tweeted one person.
"Thankfully I get more (and more regular) sleep these days. Thanks for validating what we knew all along, Michelle".
"He doesn't play games fellas, that's a very attractive quality", she said.
Even though she got in to Princeton she still remembers the feelings of doubt that it provoked.
"We are by no means suggesting Sandberg intended to blame women for inequality", researchers wrote.
PA Wire/PA Images The Duchess of Sussex with the women of the Hubb Community Kitchen at Al Manaar Muslim Cultural Heritage Centre in West London in the aftermath of the 2017 Grenfell Tower fire. There were 19 countries run by women when Lean In was published.