Brown's win robbed Democrats of the crucial 60th Senate vote they need to pass the healthcare bill and sent shudders of fear through Democrats facing tough races in November's congressional elections.
What once seemed an easy Democratic victory turned into a desperate scramble in the last few weeks as Brown surged ahead of Democratic state Attorney General Martha Coakley on voter fears over the economy, the healthcare bill and Obama's agenda.
Brown, a Massachusetts state senator, said he would be the pivotal 41st Republican vote against the healthcare overhaul in the 100-member Senate.
"People don't want this trillion-dollar healthcare plan that is being forced on the American people," Brown told cheering supporters at a Boston hotel who chanted "41" and "Seat him now."
He said voters rejected the closed-door deals that were driving the healthcare debate, and he took satisfaction in proving the experts -- and Democrats -- wrong.
"They thought that they owned this seat. They thought that they couldn't lose," Brown said. "You all set them straight."
Brown's upset with 52 percent of the vote in heavily Democratic Massachusetts raised the specter of large losses for Democrats across the country in November and left the party scrambling to find answers.
"Anyone who has been out on the campaign trail has seen the anger," Coakley, who was criticized for running a weak campaign, told a room of dispirited supporters at a Boston hotel. "I am heartbroken at the result."
Obama, who won almost 62 percent of the state's vote in the 2008 presidential election, made a last-minute appeal in Massachusetts on Sunday to try to ignite enthusiasm for Coakley's campaign to replace the late Senator Edward Kennedy, a Democratic icon and longtime champion of healthcare reform.
In Washington, Obama spokesman Robert Gibbs said the president called Brown after the result.
"The president told Senator Brown that he looks forward to working with him on the urgent economic challenges facing Massachusetts families and struggling families across our nation," Gibbs said in a statement.