Kevin Ryan joined Newsom's administration about two years ago, to head the office tasked with collaborating with local law enforcement agencies and community groups to help develop public safety policy for the mayor.
Ryan was previously the U.S. attorney in San Francisco, but was among several U.S. attorneys fired by the Bush administration in 2006.
In a statement today, Newsom thanked Ryan for his service.
"His counsel and dedication were key to reducing violent crime in the city," Newsom said.
In his resignation letter, Ryan mentioned his office's work on Police Department reform, the search for a new police chief, the review of the city's sanctuary ordinance and several violence prevention projects.
"I am very proud of the fact that since my tenure at MOCJ, San Francisco has become a safer city," Ryan said, noting a dramatic reduction in homicides and other violent crimes in the past year.
Ryan's resignation is effective Dec. 18.
On Monday, Newsom's chief spokesman /*Nathan Ballard*/ also submitted his resignation after nearly three years at the position. He will leave in February.