The bill would provide a way for millions of undocumented residents to gain a chance at citizenship and expand visas for workers as well as beef up security along the U.S. border with Mexico.
The vote was two short of what authors of the measure had wanted to pressure House Republicans to act and was identical to the vote ending debate on the issue.
"Make no mistake about it. The support this bill has generated here in the Senate will be impossible to ignore," Sen. Charles Schumer, D-N.Y., told The Hill. "I believe the support this bill will receive today in the Senate will propel it to pass the House and be placed for signature on the president's desk by the end of the year."
The legislation still has a rough row to hoe for it to become law. Many House Republicans oppose granting legal status to millions of immigrants already in the United States illegally.
In his weekly news conference, House Speaker Speaker John Boehner said Thursday any immigration legislation, including a conference report with the Senate, must win the support of a majority of his caucus.
"For any legislation, including a conference report, to pass the House, it's going to have to be a bill that has the support of a majority of our members," Boehner said, reiterating that the House would not just take up and vote on the Senate bill.
Sen. Charles Schumer, D-N.Y., the lead Democratic author of the bill, said he was pleased with the outcome despite missing his 70-vote goal.
"We wanted to get a significant number of Republicans to vote for the bill," he told MSNBC. "And what does that mean? It means that when the bill goes to the House, there's going to be pressure on them to do something. So we're feeling pretty good about how we did."
Among other things, the comprehensive bill would put an estimated 8 million illegal immigrants on a path to citizenship and spend $46 billion to tighten the nation's borders. It would also increase the number of visas for high-skilled and agricultural workers, and give more weight to educational and employment factors in granting visas.
Meanwhile, pro-immigrant groups say channeling more resources to U.S-Mexican border security is costing support among their ranks.
Advocates protested in several cities this week to denounce the Senate-endorsed plan to pump $40 billion into enforcement measures over the next decade, including 18,000 more Border Patrol agents and 700 more miles of fence, The New York Times reported Wednesday.
Going further, leaders of Presente.org, the nation's largest online Latino advocacy organization, now oppose the bill altogether, saying in a statement they could not "in good conscience" stand by the measure if it is also "guaranteed to increase death and destruction through increased militarization of the border."