His departure was widely expected as Bolton works to build his own team.
Trump often clashed with former national security adviser H.R. McMaster, who gave long-winded, didactic briefings and came under fire from Trump allies.
Bolton is reportedly considering merging the NSC and Homeland Security Council within the White House, a national security source told Fox News.
"We wish Nadia and her family the best".
Bossert's resignation follows the departure of now-former Trump NSC spokesman Michael Anton Monday. She submitted her resignation on Tuesday, according to a copy of her resignation letter obtained by CNN, and a senior White House official said she will remain in her role until April 27 to assist with the transition.
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.
The NSC primarily focuses on US foreign policy and nuclear proliferation, while the HSC focuses on national defense-related issues like terrorism and border security.
She was tapped in January to take over for Dina Powell, who made a decision to step down past year as Deputy National Security Adviser. Bolton served as USA permanent representative to the United Nations from 2005 to 2006, and as undersecretary of state for arms control and worldwide security from 2001 to 2005. He took over for K.T. McFarland, the deputy to Trump's first national security adviser, Michael Flynn.