Attorney-General Alberto Gonzales, another member of Bush's inner circle, resigned under pressure in August.
Bush said in a statement that Townsend "has always provided wise counsel on how to best protect the American people from the threat of terrorism".
"She has been a steady leader in the effort to prevent and disrupt attacks and to better respond to natural disasters," the president said, giving no reason for her departure.
Townsend, who served four and a half years in a post created after attacks in the United States on September 11, 2001, had also been a prosecutor in New York and deputy national security adviser.