He is the latest in a string of senior Justice Department officials involved in the war against terror to quit the government agency.
Thompson, currently the highest ranked black person in US law-enforcement, helped lead the government's anti-terror campaign.
The pressure and gruelling hours involved in protecting the country from attack are thought to be the cause of his departure.
He was also personally charged by President George W Bush to head a crack down on corporate fraudsters, overseeing prosecutions against officials at Enron Corp.
Thompson, 58, will likely take a job at the Brookings Institution think tank, an unidentified Justice Department official told CNN.
Thompson is the fourth in a slew of senior officials to have resigned from the Agency in recent months.
Others include Michael Chertoff, who headed the criminal division, Viet Dinh, who ran the office of legal policy and authored the antiterrorism USA Patriot Act, and Alice Fisher, the top deputy in the criminal division.