The 60-39 vote cleared the way for a bruising, full-scale debate beginning after Thanksgiving on the legislation, which is designed to extend coverage to roughly 31 million who lack it, crack down on insurance company practices that deny or dilute benefits and curtail the growth of spending on medical care nationally.
The spectator galleries were full for the unusual Saturday night showdown, and applause broke out briefly when the vote was announced. In a measure of the significance of the moment, senators sat quietly in their seats, standing only when they were called upon to vote.
In the final minutes of a daylong session, Majority Leader Harry Reid, D-Nev., accused Republicans of trying to stifle a historic debate the nation needed.
"Imagine if, instead of debating whether to abolish slavery, instead of debating whether giving women and minorities the right to vote, those who disagreed had muted discussion and killed any vote," he said.
The Republican leader, Sen. Mitch McConnell of Kentucky, said the vote was anything but procedural - casting it as a referendum on the bill itself, which he said would raise taxes, cut Medicare and create a "massive and unsustainable debt."
For all the drama, the result of the Saturday night showdown had been sealed a few hours earlier, when two final Democratic holdouts, Sens. Mary Landrieu of Louisiana and Blanche Lincoln of Arkansas, announced they would join in clearing the way for a full debate.
"It is clear to me that doing nothing is not an option," said Landrieu, who won $100 million in the legislation to help her state pay the costs of health care for the poor.
Lincoln, who faces a tough re-election next year, said the evening vote will "mark the beginning of consideration of this bill by the U.S. Senate, not the end."
Both stressed they were not committing in advance to vote for the bill that ultimately emerges from next month's debate.
Of particular contentiousness to moderates is a provision for the government to sell insurance in competition with private companies, subject to state approval - a part of Reid's bill expected to come under significant pressure as the debate unfolds.
Even so, their announcements marked a major victory for Reid and the White House in a year-end drive to enact the most sweeping changes to the nation's health care system in a half-century or more.
At the White House, press secretary Robert Gibbs issued a statement saying the president was gratified by the vote, which he says "brings us one step closer to ending insurance company abuses, reining in spiraling health care costs, providing stability and security to those with health insurance, and extending quality health coverage to those who lack it."
The legislation would require most Americans to carry insurance and provide subsidies to those who couldn't afford it. Large companies could incur costs if they did not provide coverage to their workforce. The insurance industry would come under significant new regulation under the bill, which would first ease and then ban the practice of denying coverage on the basis of pre-existing medical conditions.
Congressional budget analysts put the legislation's cost at $979 billion over a decade and said it would reduce deficits over the same period while extending coverage to 94 percent of the eligible population.
At its core, the legislation would create insurance exchanges beginning in 2014 where individuals, most of them lower income and uninsured, would shop for coverage. The bill sets aside hundreds of billions of dollars in tax credits to help those earning up to 400 percent of poverty, $88,200 for a family of four.
The House approved its version of the bill earlier this month on a near party line vote of 220-215, and Reid has said he wants the Senate to follow suit by year's end. Timing on any final compromise was unclear.
All 58 Senate Democrats and two independents voted to advance the bill. All 39 votes in opposition were cast by Republicans. GOP Sen. George Voinovich of Ohio was the only senator not to vote. Montana Sen. Max Baucus, the chairman of the Senate Finance Committee who has labored on health care for more than a year, flew in from his home state on a government plane for the vote and was returning afterward to be with his ailing mother.
While timing made Landrieu and Lincoln the final two Democrats to announce their intentions, Sen. Paul Kirk of Massachusetts had a clear claim as the 60th vote.
Appointed to office this fall after the death of Kennedy, who championed health care issues for decades, Kirk said he spoke for those "who for so many years revered and loved and elected and re-elected (him) ... that I think they're all - they all, as we do, have him in our minds and our hearts tonight. ..."
Sen. Chris Dodd, D-Conn., echoed those sentiments later in the evening when he referred to Kennedy's "lifelong quest" for national health care and said "tonight and in the days to come we will pay him the highest compliment by fulfilling that" goal.
At a post-vote news conference, Reid said he had telephoned Kennedy's widow, Vicki, with the news.
In hours of debate before the Saturday evening vote, a few Republicans piled copies of the 2,0974-page bill on their desks while others criticized it as a government takeover of health care and worse.
"Move over, Bernie Madoff. Tip your hat to a trillion-dollar scam," said Sen. Kit Bond, R-Mo., likening the bill's supporters to the imprisoned investor who fleeced millions.
In her remarks, Landrieu said, "I've decided that there are enough significant reforms and safeguards in this bill to move forward, but much more work needs to be done." She also touted the $100 million included in the legislation to help her state cover its costs under Medicaid, the state-federal health care program for the poor.
Lincoln referred repeatedly to the political controversy surrounding the issue. She said $3.3 million has already been spent by outside groups advertising either for or against health care legislation, and said, "these outside groups seem to think that this is all about my re-election. I simply think they don't know me very well."
To finance the expanded coverage, Reid proposed higher taxes as well as cuts totaling hundreds of billions of dollars in projected Medicare payments. Hardest hit would be the private insurance Medicare plans, although providers such as home health agencies would also receive significantly less in future years than now estimated.
The bill raises payroll taxes on incomes over $200,000 for individuals and $250,000 for couples. Reid eased the impact of an earlier proposal to tax high-value insurance plans, which has emerged as one of the principal methods for restraining the growth in health costs.
The bill includes tax increases on insurance companies, medical device makers, patients electing to undergo cosmetic surgery and drugmakers.
Associated Press writer Donna Cassata contributed to this article.