By a vote of 60 to 38, backers squeezed out the minimum votes needed to clear a Republican roadblock in the Senate.
Senate leaders set a series of final votes for 2 p.m., with passage looking assured. President Barack Obama, who proposed reforms more than a year ago, has said he wants to sign the measure into law next week.
Republicans who largely oppose the measure could delay a vote until Friday evening, though they are unlikely to do so.
The House of Representatives has already approved the bill, which tightens regulation across the financial industry in an effort to avoid a repeat of the 2007-2009 financial crisis.
The legislation would establish new consumer protections, give regulators greater power to dismantle troubled firms, and limit a range of risky trading activities in a way that would curb bank profits.
With Republicans poised for big gains in the November congressional elections, Democrats are eager to show voters that they are cracking down on an industry that touched off the worst recession in 70 years.
I regret I can't give you your job back, restore that foreclosed home, put retirement monies back in your account, said Democratic Senator Christopher Dodd, one of the bill's chief authors. What I can do is to see to it that we never, ever again go through what this nation has been through.
It is not clear whether voters will give Democrats credit.
The public's awareness and understanding of financial regulation is very low, according to a new poll from Ipsos released on Thursday.
Of those polled, 38 percent had never heard of the reform, while 33 percent had heard of it but know nothing about the legislation. Other polls show that voters' views of the reform fall mostly along party lines.
The bill has also won Democrats few friends on Wall Street as wealthy donors have started to steer more campaign contributions to Republicans.
FEW CORNERS OF INDUSTRY UNTOUCHED
The Dodd-Frank bill, named for Dodd and Representative Barney Frank, its chief author in the House, leaves few corners of the financial industry untouched.
Mortgage brokers, student lenders and other financial firms would have to answer to a new consumer-protection authority, though auto dealers will escape scrutiny.
Regulators, who scrambled to contain the damage from failing firms like Lehman Brothers in the 2007-09 crisis, would have new authority to dismantle troubled firms if they threaten the broader economy.
A council of regulators would monitor big-picture risks that regulators missed ahead of the past crisis.
Large banks would face new limits on risky trading activities, and many would have to set aside more capital to help them ride out times of crisis.
Large private-equity and hedge funds will face more scrutiny from federal regulators, and credit-rating agencies could potentially see their entire business model upended.
Much of the $615 trillion over-the-counter derivatives market will be routed through more accountable and transparent channels, and banks would have to spin off the riskiest of their swaps clearing desk operations.
Wall Street deployed an army of lobbyists to derail or weaken the bill, but they were undermined by the industry's tone-deaf decision to award fat bonuses to executives only months after the government put up $700 billion in bailout funds.
SOWING REGULATORY UNCERTAINTY
Most Republicans have firmly opposed the bill, arguing it is an intrusive overreach that fails to address problems in the housing market that spurred the crisis.
But as the measure moves closer to becoming law, a new criticism has emerged: the 2,300-page bill is not specific enough.
Even after Obama signs the measure into law, financial firms will face years of uncertainty as regulators put it into effect, business groups and Republicans point out.
It's just this type of uncertainty that will deter lending and freeze up credit, Senate Republican Leader Mitch McConnell said. The administration and its Democrat allies in Congress have taken a crisis and used it, rather than solving it.
The bill mandates 533 new regulations, 60 studies and 94 reports, and financial firms are likely to curtail their lending until they see how they will be affected, the U.S. Chamber of Commerce says.
The U.S. Treasury, which would head the council of regulators and temporarily direct the new consumer protection agency, has already begun a rigorous planning process in an effort to swiftly implement reforms, the Treasury's No. 2 official told an industry group in New York.
That work cannot be done overnight. It will take time, Deputy Treasury Secretary Neil Wolin said. But we are prepared to move on to the next stage with speed.
The uncertainty factor even gives some Democrats pause. Senator Ben Nelson, one of the chamber's most conservative Democrats, earlier in the week threatened to withdraw his support for the bill for that reason before relenting.
Dodd said his Senate Banking Committee may hold hearings later this year on regulators' plans for implementing the bill.