"I'm very grateful I have had the chance to serve but I think it's time for others to step up," Clinton said in an interview aired on NBC's "Today."
"I am very privileged to have had the opportunity to serve my country," she said. "I've made my contribution. I've done the best I can. I want to try other things."
Clinton had said on previous occasions she had no plans for a presidential run, expressing her desire to return to private life.
Clinton, 63, told "Today" she would leave her post as the top U.S. diplomat at the end of Obama's first first term.
Despite very trying circumstances when Obama took office and she was confirmed secretary of state, Clinton said she hoped she will be remembered for reasserting American leadership.
"We are going to lead despite other countries coming to the forefront. We are going to lead because America is destined to lead."
If other leaders think America is in decline, "they're badly mistaken," Clinton said. "We cannot abdicate leadership around the world because when we do it'll come back to bite us."
She said she answered Obama's call to become secretary of state despite an acrimonious, hard-fought Democratic primary cycle "because we both love this country."
"We have to be bigger than politics," she said.