Obama will reportedly nominate Office of Management and Budget Director Sylvia Mathews Burwell to replace the 65-year-old former governor of Kansas.
Sebelius has served as health secretary since 2009, and has spent the last five years leading the charge for Obama's controversial health care law.
Obamacare's online exchange, Healthcare.gov, has been beset with technical difficulties since it launched last October.
Officials also told the Times that Sebelius was not asked to leave, but had decided to resign on her own.
The news of Sebelius' departure came the same day she announced that 7.5 million Americans had signed up for health insurance through the exchanges.
[NY Times, Washington Post]