Majority Leader Tom Daschle, a South Dakota Democrat, said the vote was an important test of Bush administration efforts to weaken environmental protections.
"We are just not going to allow Republicans to destroy the environment," Daschle told reporters.
CBS News Chief Washington Correspondent Bob Schieffer reports that, with so much uncertainty in the Middle East, the Bush administration saw this as a national security issue, a way to lessen U.S. dependence on Arab oil.
The Senate "missed an opportunity to lead America to greater energy independence," said White House press secretary Ari Fleischer.
Fleischer said President Bush would continue to fight for opening the refuge. But he sidestepped a question on whether Mr. Bush would sign an energy bill that does not include refuge drilling.
Eight Republicans joined most Democrats in opposing the drilling measure. Five Democrats supported the drilling amendment, offered by the two Alaska senators.
While the House last summer approved drilling in the wildlife refuge, that bill will have to be reconciled with legislation expected to be passed by the Senate. Drilling supporters in Congress and at the White House have worried that a poor showing in the Senate might jeopardize getting a drilling measure out of the House-Senate negotiations.
Drilling supporters argued the refuge's oil was essential for America's energy security and its development would produce tens of thousands of jobs.
But Democrats said no oil would flow for a decade and would have little impact in oil imports or fuel prices.
"Development (of the refuge) would irreversibly damage this natural resource," said Sen. Joe Lieberman, D-Conn., a leader of the filibuster.
Murkowski said that without ANWR drilling "there is not one single thing in this energy bill that increases oil production. "One can only wonder what the OPEC cartel is thinking today," he said after the Senate vote, alluding to the foreign oil producers and U.S. reliance on oil imports.
Sen. Ted Stevens, R-Alaska, blamed "radical environmental organizations" for shutting off a needed energy resource. His state would receive half of the royalties from oil taken from the refuge.
An attempt to gain some pro-drilling votes by funneling money from future Arctic refuge oil leases to help steelworkers and coal miners was rejected 64-36.
Sen. Jay Rockefeller, D-W.Va., who has led efforts in the Senate to try to help steelworkers facing economic hard times, called the proposal "an empty promise" that could later be dropped, and urged its rejection.
Drilling for the billions of barrels of oil believed to lie beneath the 1.5 million-acre coastal plain of the sprawling refuge has been the most contentious issue facing senators trying to craft energy legislation.
Mr. Bush repeatedly has argued that the oil can be extracted without harming the environment or wildlife, and he has cited Iraq's current oil embargo as proof that new drilling is needed more than ever.
But environmentalists and many Senate Democrats — as well as a handful of GOP senators — argued the oil can be found elsewhere without risking the refuge and its wildlife, including a herd of 123,000 caribou that calves each year on the coastal plain.
During two days of sometimes emotional debate, drilling supporters assailed "radical" environmentalists who have opposed drilling and talked as much about the recent turmoil in the Middle East and Iraq's suspension of oil shipments as about the refuge itself.
"There's an inferno in the Mideast and we're importing more than 50 percent of our oil," said Murkowski, arguing that extracting the oil in ANWR is a matter of national security because it will cut the need for imports.
Drilling opponents scoffed at that argument.
"I've learned a few lessons about national security as a soldier and a senator, but the mathematics I learned in elementary school prove that Arctic drilling won't make a difference for national security," said Sen. John Kerry, D-Mass., a decorated Vietnam veteran.
Kerry said the United States has 3 percent of the world's oil and uses 25 percent of the supply. "The solution is not in the Arctic," he said.
If energy security was the issue, he said, Republicans should have supported his proposal, which was rejected earlier, to require increased automobile fuel efficiency.
The drilling issue has attracted intense lobbying by environmentalists who have made it their No. 1 issue. Stung last summer when the Republican-controlled House passed an energy bill that would open the refuge to oil development, they vowed to press the issue in the Democratic-controlled Senate.
"Oil rigs do not belong in the Arctic Wildlife Refuge," said Mark Van Putten, president of the National Wildlife Federation.
Geologists believe ANWR's 1.5 million-acre coastal plain may contain 11.6 billion barrels of oil, almost as much as has been taken from nearby Prudhoe Bay.
At peak production, ANWR would supply about 1.9 million barrels a day, according to the Interior Department estimates. The United States today uses 19 million barrels a day, 57 percent of that from imports.