Thirteen Republicans broke with their top two leaders and joined 56 Democrats and two independent in providing the necessary two-thirds vote to approve the treaty. The vote was 71-26.
The accord, which still must be approved by Russia, would restart onsite weapons inspections as successors to President Ronald Reagan have embraced his edict of "trust, but verify."
Vice President Joe Biden presided over the Senate and announced the vote. Secretary of State Hillary Rodham Clinton observed the vote from the Senate floor. Both had lobbied furiously for the treaty's approval.
"The question is whether we move the world a little out of the dark shadow of nuclear nightmare," Foreign Relations Committee Chairman John Kerry asked his colleagues moments before the historic tally.