The chamber agreed to move forward with debate on a bill that would force President Barack Obama to approve the controversial Canadian oil infrastructure.
The vote reflects the power of the new Republican majority following the midterm elections, and is the first piece of legislation advanced in the new congressional session.
Similar legislation had never managed to attain the filibuster-proof 60 votes under Democratic control — and, on Monday, it cleared that hurdle with 63 votes.
But there's a fly in the ointment for pipeline supporters: Obama has signalled he'll veto the bill because he says it's his responsibility, not lawmakers', to approve or reject cross-border infrastructure.
The vote will likely unleash a lively legislative scramble.
Lawmakers will attempt to get their hands on the bill, to stuff it with amendments either reflecting their own priorities or designed to gain a few crucial votes. It takes 67 votes to strike down a presidential veto. Major amendments are likely.
Some on the left are expected to propose other energy measures or Buy American clauses for pipeline materials. On the right, there's some early chatter about loosening coal regulations or relaxing a decades-old U.S. restriction on oil exports.
Only a fraction of Democrats support the bill. Many are expressing exasperation that a foreign company's privately owned oil pipeline is the No. 1 piece of legislation introduced by the new majority party.
Several members listed a number of other pressing national priorities that the Republicans could have pursued instead, like a highway-funding bill that would create thousands of times more jobs than Keystone.
"Thirty-five (permanent) jobs for Americans — you've got to be kidding. This is what you've got for us?" pipeline opponent Barbara Boxer, a California Democrat, told the chamber after the vote.
"The first bill that they take up symbolizes their priorities. You have to wonder, why are they doing this? I believe I know the answer. This is really a big hug and a big kiss to big oil, and Canadian interests. That's what it's about."
Some of the most vocal Keystone opponents, like Boxer and Hawaii's Brian Schatz, actually received big campaign donations from environmental groups or the alternative-energy industry.
Those ties drew a disparaging comment from the new chamber leader, Mitch McConnell. The new Senate speaker said it's time to move forward, now that a Nebraska court case over the route is over.
"(This Nebraska court decision) has to be the last conceivable pretext to veto the Keystone jobs bill," McConnell said.
"We'll send a bipartisan jobs bill to the president.... It may force the president to finally make a difficult choice — between jobs and the middle class, versus the demands of powerful special interests."
Speaking of special interests, money flows both ways. And the cash rained mightily on McConnell's re-election campaign last year.
Among the 535 members of Congress, McConnell was the No. 5 recipient of donations from the oil and gas sector during the previous Congress, according to the Center for Responsive Politics.
Before Christmas, he announced Senate Bill 1 — legislation to approve the Keystone XL pipeline.