Obama made the remarks as she addressed the South by Southwest festival in Austin yesterday, Texas, where she introduced a song for charity to support a UN-backed campaign to improve education access for the 62 million unschooled girls around the world.
"I will not run for president. Nope, nope, not going to do it," she said in response to a question.
"There is so much that I can do outside of the White House, and sometimes there is much more that you can do outside the White House without the constraints, and the lights and the cameras, and the partisanship," she added.
Part of the first African American first family, the 52-year-old is a Harvard-educated lawyer who has made no secret of her distaste for the glare of political life and has tried to steer clear of controversy, instead focusing on issues such as fighting obesity.
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She said that she also wanted her daughters, Malia and Sasha, to live elsewhere after what will be eight years in the White House.
"They've handled it with grace and poise but enough is enough," she said.
Hillary Clinton, another highly educated first lady, was active in her husband's administration and in his final year ran successfully for a US Senate seat in New York.
She is the frontrunner for the Democratic nomination in the 2016 race for the White House.
Obama at South by Southwest released the song "This Is For My Girls" by Diane Warren, which features contributions by major female singers including Kelly Clarkson, Missy Elliot and Janelle Monae.
Obama said she was touched by visits around the world with girls who travel great distances or risk violence to go to school.