Mrs Clinton has officially tendered her resignation to President Barack Obama.
In her letter, she said she was more convinced than ever of America's strength as a global leader and its potential to be a force for good.
Mrs Clinton, 65, leaves the post after four years, visits to 112 countries and nearly a million air miles.
She will be replaced by John Kerry, a Massachusetts senator, who was sworn in at a private ceremony on Friday.
The former first lady is now discussed as a possible candidate for the 2016 presidential election.
Mrs Clinton said leading the agency as the 67th US Secretary of State had been a "unique and singular, exciting and challenging" experience