Born in Hinton, Burwell graduated as valedictorian from Hinton High School and later earned a degree in government from Harvard University. She was a Rhodes Scholar at Oxford, studying philosophy, politics, and economics. In the Clinton Administration, Burwell held key roles, including staff director for the National Economic Council and deputy chief of staff.

Afterward, she worked at the Bill and Melinda Gates Foundation and Walmart Foundation, then returned to public service as Director of the Office of Management and Budget (OMB) under President Obama. In 2014, she became Secretary of Health and Human Services, managing Medicare, Medicaid, and the Affordable Care Act. From 2017 to 2024, she served as the first female president of American University.