Nadia Schadlow tendered her resignation in a letter Tuesday.
She was tapped in January to take over for Dina Powell, who chose to step down previous year as Deputy National Security Adviser.
Her resignation is likely to evoke some concern in foreign policy circles in Washington, where Schadlow has been viewed as one of the rare, reliable steady hands guiding foreign policy in the Trump White House.
Schadlow was considered close to Trump's outgoing National Security Adviser, General H.R. McMaster, and played a key role in his effort to produce a national security strategy document for the administration.
The Trump administration announced another major departure from its senior ranks on Tuesday, with the resignation of Thomas P. Bossert as President Trump's chief adviser on homeland security.
This is a breaking news story and will be updated if more information becomes available.
Schadlow's departure is not expected to be the last as Bolton puts his imprint on the National Security Council.
"Dr. Rick Waddell plans to step down from his position at the White House", said White House spokesperson Lindsay Walters.
Bossert's most prominent role at the White House came after a series of devastating hurricanes hit several U.S. states and Puerto Rico last fall, when Bossert served as the White House's point person for the emergency response and rebuilding efforts.
Bossert, who also served in the George W. Bush administration, wasn't a marquee name, but he was liked by Trump, senior administration officials said, and often defended his agenda in meetings and in interviews with the media. Bolton officially began at the White House on Monday.