The vote had been delayed for a week as Democratic senators hammered the Justice Department for refusing to release an unedited copy of a May 2004 e-mail from FBI agents seeking guidance about questioning terror suspects held at Guantanamo Bay, reported the Associated Press.
Chertoff, a federal appeals court judge, headed the Justice Department's criminal division during the government investigation immediately following the Sept. 11, 2001, terror attacks.
He replaces Tom Ridge, who led the Department of Homeland Security since its creation after the attacks and stepped down on Feb. 1.
Chertoff told lawmakers during his confirmation hearings that he had no knowledge of the contents of the FBI memo, or who sent it. Chertoff also denied approving any harsh interrogation techniques that violate anti-torture laws, according to the AP.
Sen. Carl Levin, D-Mich., said his demand for the FBI memo was to merely assure congressional oversight and was not meant to challenge Chertoff's integrity.
Senate Homeland Security and Governmental Affairs Committee Chairwoman Susan Collins, R-Maine, said the memo is irrelevant to Chertoff's nomination and urged lawmakers to take his assurances at face value.
The 98-0 vote completed Senate action on President Bush's second-term Cabinet, though he still must fill some key, non-Cabinet jobs -- like the newly created post of director of national intelligence, Reuters reported.