Mastromonaco wanted to leave earlier in the president's second term to pursue other career options, according to aides, but the president resisted the idea and persuaded her to stay on longer.
Her departure was first reported by the Associated Press on Saturday night.
In November she married her longtime boyfriend, creating one of the Beltway's most influential power couples: David Krone, chief of staff to Senate Majority Leader Harry M. Reid (D-Nev.). The small service was held at the Supreme Court.
Mastromonaco helped set up Obama's Senate office in 2005, worked on his first presidential bid and has served in the White House since he took office. She weighs in on strategic decisions related to both domestic and international policy. She also takes care of the president's personal priorities, from scheduling basketball games to time with his family.
"When he thinks his life is out of control, or there's too much going on, he calls Alyssa," Obama's former senior adviser Pete Rouse told The Washington Post in 2008.
Rouse, who had also served as one of the president's top aides since the start of his Senate career, took his leave in January. With Mastromonaco's exit, Obama's circle of longtime confidants has become even smaller.
Philip Rucker contributed to this report.