The White House shocked Washington by announcing that James Comey "has been terminated and removed from office".
But Democrats said he was fired because the FBI was investigating alleged links between the Trump campaign and Russia.
The move came as it emerged Mr Comey gave inaccurate information about Mrs Clinton's emails to Congress last week.
President Trump wrote in a letter to Mr Comey that he agreed with US Attorney General Jeff Sessions' recommendation that "you are not able to effectively lead the Bureau".
Mr Sessions said the Department of Justice was "committed to a high level of discipline, integrity, and the rule of law", and "a fresh start is needed".
The White House said the search for a successor would begin immediately.