White House Chief of Staff Andrew Card, administered the oath of office late on Wednesday, immediately making Rice the new top US diplomat and allowing her to get to work at the Department of State.
The US Senate voted 85-13 to clear her nomination, with two abstentions. Rice served until now as President George Bush's national security adviser.
She becomes the first black woman to head US foreign policy.
The White House said she would report for duty at the State Department on Thursday, and a ceremonial swearing-in would be held later in the week.
After the Senate confirmation, Bush said Rice will be "a great secretary of state .. I am honoured to be working with her. And I look forward to spreading freedom and peace".
But Democratic senators said Rice had repeatedly deceived Congress and was responsible for decisions they said have mired the US in a conflict that has hurt efforts to fight terrorism worldwide.
Republicans accused Democrats, however, of politicising the confirmation by demanding a full day of Senate floor time in which they blasted Bush's Iraq policies.
The White House had wanted her to be confirmed quickly last week when Bush was sworn in for a second term.