Greeted by screams and cheers, she talked about her own working-class background in Chicago in a speech at Mulberry School for Girls.
The visit is part of her global initiative to promote female education.
Accompanied by her two daughters, she also met Prince Harry at Kensington Palace and had tea at Downing Street.
Mrs Obama told pupils at the school in Tower Hamlets the world needed "more girls like you to lead our parliaments, our courtrooms and universities".
In a speech, she said: "With an education from this amazing school you all have everything, everything you need to rise above all of the noise and fulfil every last one of your dreams.
"And it is so important that you do that, not just for yourselves but for all of us. Because you all have a unique perspective, you have a unique voice to add to the conversation."
-BBC