The cloture vote failed 59-40.
"It was a good, heartfelt battle," said Senate Majority Leader Harry Reid (D-Nev.) after the vote, vowing to continue working on the energy bill.
"We are going to finish this bill today if at all possible."
Debate on the bill came down to two contentious provisions, one to require utility companies to use a fixed percentage of renewable energy and the other a $21 billion tax package that would have eliminated billions of dollars in tax breaks for large oil companies.
On Wednesday, the House passed a version of the bill that included both provisions.
After the failed cloture vote on Thursday morning, Reid indicated he would remove the tax title, in order to pass the rest of the energy package, which includes the first increase in Corporate Average Fuel Economy Standards in three decades.
Senate Minority Leader Mitch McConnell (R-Ky.) said his opposition to the bill centered around the tax package and the renewable energy provisions — which he calls the "twin millstones" and indicated that he could support it if the provisions were removed.
Several presidential candidates came back to Washington to help try and push the bill over the finish line, including Sen. Hillary Rodham Clinton (D-N.Y) and Sen. Barack Obama (D-N.Y).