With Vice President Joe Biden presiding in case his vote was needed to break a tie, the Senate approved the measure by 56-43. Underscoring the partisan divide that has characterized the long-running health care fight, all voting Republicans opposed the measure, as did three Democrats: Arkansas Sens. Blanche Lincoln and Mark Pryor, and Nebraska Sen. Ben Nelson.
In a dramatic nod to the late Sen. Edward Kennedy (D-Mass.), who had spent a career championing health care for all Americans, the Senate observed a moment of silence in his honor before voting.
Senate Majority Leader Harry Reid (D-Nev.) asked senators to cast their votes from their desks, a seldom-used procedure the chamber employs only for the most significant measures. Democrats did so in a bow to the initiative's importance to their party, but some Republicans did not.
Eager to get the contentious battle behind them, Democrats originally hoped the Senate's vote would ship the measure to President Barack Obama for his signature. But working with the chamber's parliamentarian, Republicans found two minor provisions in the bill - dealing with future Pell grants for low-income students - that violated congressional budget rules and were deleted from the legislation.
As a result, the bill had to be returned to the House because both chambers must approve identical legislation before it can be sent to the White House.
Obama's drive to reshape the country's health care system - capped Tuesday when he signed wide-ranging changes into law - has been a tortuous, bitterly fought journey from the start.
As if to mimic that, senators approved the bill Thursday after taking 42 consecutive roll call votes, a record for continual voting often called a "vote-a-rama." That included 41 Republican amendments, with Democrats defeating every one, and then final passage.
They voted until after 2 a.m. Thursday, then resumed the roll calls later in the morning, tallying a total of 13 hours of relentless voting.
"This has been a legislative fight that will be in the record books," Reid said before the final Senate roll call.
The Senate vote occurred as Obama used a campaign-style speech in Iowa City, Iowa, to tout the landmark health legislation and dare Republicans to follow through on repeated threats to try repealing the law.
"My attitude is, go for it" and see how voters like that, he taunted.
"If they want to have that fight, we can have it. Because I don't believe the American people are going to put the insurance industry back in the driver's seat," he said.
The legislation the Senate approved on Thursday would change the new health care law by making drug benefits for Medicare recipients more generous by gradually closing a gap in coverage, increasing tax subsidies to help low-income people afford health care, and boosting federal Medicaid payments to states.
It would kill part of the new statute uniquely giving Nebraska extra Medicaid funds - designed to lure support from that state's Sen. Ben Nelson - that had become a glaring embarrassment to Democrats. It also would ease a new tax on expensive health coverage bitterly opposed by unions and many House Democrats, while delaying and increasing a new levy on drug makers.
Besides reshaping parts of the landmark health overhaul, the legislation transforms the federal student loan program - in which private banks distribute the money - into one in which the government issues the loans directly. That produces some federal savings, which the bill uses in part to increase Pell grants to needy students.
Outnumbered and all but assured of defeat, Republicans forced votes on amendments aimed at reshaping the measure - or at least forcing Democrats to take votes that could be used against them in TV ads in the fall campaigns.
By 57-42, Democrats rejected an amendment by Sen. Tom Coburn (R-Okla.) barring federal purchases of Viagra and other erectile dysfunction drugs for sex offenders. Coburn said it would save millions of dollars, while Sen. Max Baucus (D-Mont.) called it "a crass political stunt."
Other rejected amendments would have rolled back cuts in Medicare that Democrats use for expanded health coverage, and would have required the president and other administration officials to buy health policies from new insurance purchasing exchanges the law will establish.
The landmark legislation that Obama signed Tuesday would provide health care to 32 million uninsured people, and make coverage more affordable to millions of others by expanding the reach of Medicaid and creating new subsidies. Insurance companies would be forbidden to refuse coverage to people with illnesses, individuals could buy policies on newly created exchanges and parents could keep children on their family plans until their 26th birthdays.
The $938 billion, 10-year price tag would be financed largely by culling savings from Medicare and imposing new taxes on higher income people and the insurance, drug and medical device industries.