The vote was 67-27, seven more than the 60 needed, with 15 Republicans voting to advance legislation at the top of President Barack Obama's second-term domestic agenda.
The vote came as Obama campaigned from the White House for the bill, saying, "now is the time" to overhaul an immigration system that even critics of the legislation agree needs reform.
Last-minute frustration was evident among opponents. In an unusual slap at members of his own party as well as Democrats, Republican Sen. Ted Cruz of Texas said it appeared that lawmakers on both sides of the political aisle "very much want a fig leaf" on border security to justify a vote for immigration.
Senate passage on Thursday or Friday would send the issue to the House, where conservative Republicans in the majority oppose citizenship for anyone living in the country illegally.
Some GOP lawmakers have appealed to Speaker John Boehner not to permit any immigration legislation to come to a vote for fear that whatever its contents, it would open the door to an unpalatable compromise with the Senate. At the same time, the House Judiciary Committee is in the midst of approving a handful of measures related to immigration, action that ordinarily is a prelude to votes in the full House.
"Now is the time to do it," Obama said at the White House before meeting with nine business executives who support a change in immigration laws. He added, "I hope that we can get the strongest possible vote out of the Senate so that we can then move to the House and get this done before the summer break" beginning in early August.
He said the measure would be good for the economy, for business and for workers who are "oftentimes exploited at low wages."
As for the overall economy, he said, "I think every business leader here feels confident that they'll be in a stronger position to continue to innovate, to continue to invest, to continue to create jobs and ensure that this continues to be the land of opportunity for generations to come."
Opponents saw it otherwise. "It will encourage more illegal immigration and must be stopped," Cruz exhorted supporters via email, urging them to contact their own senators with a plea to defeat the measure.
Leaving little to chance, the U.S. Chamber of Commerce announced it was launching a new seven-figure ad buy Monday in support of the bill. "Call Congress. End de facto amnesty. Create jobs and economic growth by supporting conservative immigration reforms," the ad said.
Senate officials said some changes were still possible to the bill before it leaves the Senate - alterations that would swell the vote total.
At the same time, Sen. Roger Wicker, R-Miss., who voted to advance the measure during the day, said he may yet end up opposing it unless he wins a pair of changes he is seeking.
Senate Democrats were unified on the vote.
Republicans were anything on a bill that some party leaders say offers the GOP a chance to show a more welcoming face to Hispanic voters, yet tea party-aligned lawmakers assail as amnesty for those who have violated the law.
Among potential 2016 presidential contenders, Sen. Marco Rubio of Florida was an enthusiastic supporter of the bill, while Cruz was an outspoken opponent.
The non-partisan Congressional Budget Office has estimated the legislation will reduce the deficit and increase economic growth in each of the next two decades. It is also predicting unemployment will rise slightly through 2020, and that average wages will move lower over a decade.
At its core, the legislation in the Senate would create a 13-year pathway to citizenship for an estimated 11 million immigrants living illegally in the United States. It also calls for billions of dollars to be spent on manpower and technology to secure the 2,000-mile border with Mexico, including a doubling of the Border Patrol with 20,000 new agents.
The measure also would create a new program for temporary farm laborers to come into the country, and another for lower-skilled workers to emigrate permanently. At the same time, it calls for an expansion of an existing visa program for highly-skilled workers, a gesture to high tech companies that rely heavily on foreigners.
In addition to border security, the measure phases in a mandatory program for employers to verify the legal status of potential workers, and separate effort to track the comings and goings of foreigners at some of the nation's airports.
The legislation was originally drafted by a bipartisan Gang of 8, four senators from each party who negotiated a series of political tradeoffs over several months.
The addition of the tougher border security provisions came after CBO informed lawmakers that they could potentially spend tens of billions of dollars to sweeten the bill without fearing higher deficits.
The result was a series of changes negotiated between the Gang of 8 and Republican Sens. John Hoeven of North Dakota and Bob Corker of Tennessee. Different, lesser-noticed provisions helped other lawmakers swing behind the measure.
In a speech on the Senate floor, Sen. Charles Grassley, R-Iowa, likened some of them to "earmarks," the now-banned practice of directing federal funds to the pet projects of individual lawmakers.
He cited a provision creating a $1.5 billion jobs fund for low-income youth and pair of changes to benefit the seafood processing industry in Alaska. Sen. Bernard Sanders, I-Vt., issued a statement on Friday trumpeting the benefits of the first; Alaska Sens. Lisa Murkowski, a Republican, and Mark Begich, a Democrat, took credit for the two others.
Grassley also raised questions about the origin of a detailed list of planes, sensors, cameras and other equipment to be placed along the southern border.
"Who provided the amendment sponsors with this list?" asked Grassley, who is a member of the Judiciary Committee that approved an earlier version of the bill. Homeland Security Secretary Janet Napolitano "did not provide the committee with any list. Did Sikorsky, Cessna and Northrup Grumann send up a wish list to certain members of the Senate?"
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