National Security Adviser Gen James Jones is stepping down and will be replaced by his deputy, Tom Donilon.
President Barack Obama announced the high-level staff changes at the White House on Friday.
Gen Jones's announcement had been widely expected, as Mr Obama nears two years in the White House.
It follows news of the departure of several other senior White House advisers, including political aides and top economic adviser Larry Summers.
"You complete this assignment knowing that your country is safer and strong," Mr Obama told Gen Jones at a televised press conference. "I thank you and the American people thank you."
The president described Gen Jones's successor, Mr Donilon, as "very capable".
Gen Jones, a former Marine Corps general, is the first high-level member of Mr Obama's national security team to depart.
US Secretary of State Hillary Clinton said in a statement: "His leadership was crucial in winding down the combat mission in Iraq, refocusing the war in Afghanistan, and advancing our nation's interests and values around the world."
In recent weeks, Mr Obama's chief of staff Rahm Emanuel left to run for mayor of Chicago and senior political adviser David Axelrod announced he would be leaving in the spring to plan the president's 2012 re-election bid.
Mr Summers, Mr Obama's top economic adviser, announced last month he would leave at the end of the year to return to Harvard University.
Staff departures are not unusual at this point in a president's term, nearly halfway through the four years.
Gen Jones is seen as close to the president, while Mr Donilon, a veteran Democratic political hand and former chief of staff to Bill Clinton's Secretary of State Warren Christopher, is not seen as part of Mr Obama's inner circle, analysts say.
A recent book by veteran reporter Bob Woodward of the Washington Post quoted Defence Secretary Robert Gates as saying Mr Donilon would be "a disaster" as a national security adviser.
But addressing reporters at the Pentagon on Friday, Mr Gates disavowed that reported criticism.
"I have thoroughly enjoyed working with General Jones and I have - and have had - a very productive and very good working relationship with Tom Donilon, contrary to what you may have read, and I look forward to continue to working with him," he said.
Gen Jones retired from the Marine Corps in 2007 after more than 40 years, taking a position as the State Department's Special Envoy for Middle East Regional Security.
He was commissioned as a Marine Corps officer in 1967, and was sent to Vietnam. He later served in command and staff positions all over the world.