Her appointment, confirmed by the Senate and sealed in a private ceremony in her Senate office on Wednesday, came as Obama moved quickly on his first day in office to shore up a team of seasoned advisers and take the nation's foreign policy in a new direction.
Obama prepared to name former Senate Democratic leader George J. Mitchell as Clinton's special envoy to the Middle East, and he placed telephone calls to regional presidents.
Obama was to join Clinton at the State Department on Thursday, where the two were to address department employees. Obama, Clinton, Vice President Joe Biden and national security adviser James Jones were to convene a closed-door meeting beforehand.
After being confirmed 94-2 by the Senate on Wednesday, Clinton delivered letters of resignation to Vice President Joe Biden, as president of the Senate, and New York Gov. David Paterson, who will chose her replacement.
Senate Majority Leader Harry Reid, a Democrat from Nevada, said her swift confirmation was an imperative.
"We face two wars abroad, a complex and unpredictable crisis in the Middle East, the nuclear ambitions of a volatile Iranian regime, together with the complexities of dealing with North Korea," he said.
While Republicans agreed that Obama should be allowed to quickly pull together his Cabinet, some remained skeptical about his plans to revamp the nation's policies on such wartime issues as detainees.
Sen. Lindsey Graham, a Republican from South Carolina, who challenged the Bush administration's detainee policy in 2006 and helped write legislation governing the new court system, said he agrees that Guantanamo Bay should be closed and a new secure location found.
But "the prison is not the problem," Graham said in a recent interview. "For all the challenges facing the nation, finding a place to put (military prisoners) is not the issue. ... Before we move them, we need to know what's going to happen to them."
Graham, a colonel in the Air Force Reserves who served in Afghanistan last month and in Iraq a year ago, said he wants to work with the new administration to make sure the rules don't become too lenient on terrorists.
"I don't want to lose sight of the fact that we're at war," he said, adding that the worst possible scenario for the new administration would be the inadvertent release of a dangerous terrorist.
Congress must help to ensure the new system "restores our image, adheres to our values and protects the nation," Graham said.
Sen. Jim DeMint, a South Carolina Republican, said he was concerned that Obama and Clinton would reverse the U.S. policy that prohibits U.S. aid to overseas groups that offer abortions.
"I do not plan to slow up this nomination, but I do find it difficult to support a nominee who I know will pursue policies so contrary to American sovereignty and the dignity of the human person," DeMint said, shortly before voting with Louisiana Republican Sen. David Vitter against Clinton's appointment.