Alyssa Mastromonaco is Obama's deputy chief of staff for operations and often described as the most influential person inside the White House who isn't well known outside of it.
She is responsible for planning presidential events, hiring staff and overseeing the White House complex.
A White House official said Mastromonaco is leaving in May to look for a job in the private sector.
The official said Obama insisted as a condition of her departure that she continue to act as an outside adviser. The official was not authorized to discuss the matter publicly and spoke on condition of anonymity.
Mastromonaco joined Obama's Senate office in February 2005 as scheduling director, and oversaw scheduling and advance for his 2008 presidential campaign and during Obama's first term at the White House. She was promoted to deputy chief of staff in 2011.
Mastromonaco is one of several of Obama's most trusted long-time advisers to leave as he enters his sixth year in office. It's a familiar pattern for second-term presidents, as aides grow tired of the pressure cooker and look for other opportunities outside the White House before the administration winds down.