The vote was 70-to-28 with around a dozen Republicans siding with the Democratic majority to approve the measure. This was an even larger number of minority party members to vote with the Democrats on the legislation than a key procedural vote earlier in the week.
Unlike that earlier vote, this one only required a simple majority to be passed.
Among those Republicans supporting the measure was Sen. Scott Brown (R., Mass.), the freshman lawmaker who was only sworn into his Senate seat earlier this month.
Democratic senators said this week that the bill, proposed by Senate Majority Leader Harry Reid, (D., Nev.) would save or create 1.3 million jobs, which if realized would be a much-needed shot in the arm for the ailing economy.
The bill's centerpiece is a tax credit for employers who hire new workers—a measure Democrats hope will motivate business owners to begin hiring again.
Employers wouldn't have to pay their share of federal payroll taxes for any new workers that have been unemployed for at least 60 days for the rest of 2010. If that worker is still on the books in a year, the business owner would receive an additional $1,000 tax credit.
Other measures in the bill are aimed at improving access to capital for small businesses, an extension of the current federal subsidy for road and bridge repairs carried out by states, and a modest expansion of federally subsidized bonds to help local governments raise funds for infrastructure projects.
Democrats said the cost of the legislation would be offset by cracking down on offshore tax evasion.
Before the Senate voted on final passage, lawmakers defeated an attempt by Republicans to block the bill.
Sen. Judd Gregg (R., N.H.), the top Republican on the budget panel and a renowned fiscal conservative, said the bill would add to federal spending at a time when the deficit is already running at historical highs.
The House must act to take up the legislation before it is finalized. Lawmakers there approved a much larger job-creation package last December, which included some of the elements of the Senate bill.
Tuesday, House Majority Leader Steny Hoyer (D., Md.) said Democratic leadership could decide to simply take up the Senate bill, but said there might be opposition from Democratic lawmakers in doing so.
Mr. Reid said on the floor of the Senate Wednesday that he hopes to get unanimous agreement from the other senators to approve a short-term extension of federal jobless benefits and subsidies for people who lost their health insurance when they were laid off from their jobs.
If that bid is rejected, Democrats are expected to move quickly to a second economic package that would likely include the benefit extensions along with other measures.
Democrats have spoken several times about wanting to move several pieces of targeted economic legislation to help spur job growth.
Heading into what most observers conclude is going to be tough mid-term elections, Democrats are aware of the need to bring down the country's unemployment rate before the November poll.
The rate stood at 9.7% in January, although that is seen to be much higher when those people who have stopped looking for work or are working part time are included.