Her departure removes a lightning rod for Republican critics as Obama and his Democrats try to retain control of the US Senate in November midterm elections, where problems with Obamacare reforms will be a top issue.
The Oct 1 launch of the new Obamacare health insurance marketplace, which was plagued by computer problems, has been condemned by Republicans as a step toward socialized medicine.
Obama has chosen Sylvia Mathews Burwell, his budget director, to replace Sebelius, the official said. She will manage the continued implementation of the Affordable Care Act, the signature legislation of Obama's two terms as president.
Obama was due to announce the change with Sebelius and Burwell at his side at a White House event at 10:45 am EDT (1445 GMT) on Friday.
Sebelius, 65, became the public face for the problem-plagued start to the enrollment period for Obamacare, which was meant to reduce the number of Americans without health insurance and cut into massive US healthcare costs.
When enrollment opened in October, a website used to shop for insurance in 36 states, HealthCare.gov, failed to work for weeks.
Even as she took responsibility for the failures, Obama stuck by Sebelius, brushing aside pressure to fire her.
"Hold me accountable for the debacle. I'm responsible," Sebelius said at an Oct. 30 hearing.
MANAGEMENT CREDENTIALS
Burwell, a former official at the Gates Foundation and Wal-Mart Foundation, helped the administration manage its response to a shutdown of the federal government brought on by a budget battle with Republicans in October. She also was a key player in talks that yielded a two-year budget agreement in December.