Brown had been pulling ahead of moderate Republican DeWine as early as June, leading the GOP to abandon efforts in the state early in the midterm campaign.
Brown picked up more votes than expected in southwest Ohio, where DeWine resides, and other conservative parts of the state.
Associated Press-operated exit polls showed that Ohio voters' opposition to the war and President Bush were key to Brown's victory.
The Democrat victory breaks away from Republican control in Ohio; all elected statewide offices had been held by Republicans, including that of Gov. Bob Taft, R-Ohio, who is not running for re-election, and state's other senator, George Voinovich, who last week urged Ohio citizens to vote for DeWine.
"The climate, as they say in politics, is not good," DeWine had acknowledged before the election, the AP reported.
DeWine had easily won re-election to the Senate in 1994 and 2000, but he had not faced a candidate who had previously won statewide election. Brown, a former Ohio secretary of state and Ohio state lawmaker, was re-elected six times to his U.S. House seat.
AP exit polls also showed that Brown received more than half of the votes from those dismayed with breaches of ethics that have plagued Republicans in the months before the midterm election, spanning Ohio Rep. Bob Ney's guilty plea after accepting gifts for favors to clients of Washington lobbyist Jack Abramoff and former Florida Rep. Mark Foley's inappropriate communications with congressional pages.
The fight for the Senate seat played out nationally in televised attack ads. In his ads, DeWine cited threats to national security that could arise because of Brown's House vote against the expansion of government surveillance authority.
Brown countered by referring to recent intelligence reports showing rising terrorism as reasons for DeWine to develop an exit strategy. Brown's ads kept the focus on DeWine's ties to President Bush and his handling of the Iraq war. Brown, who voted against 2003's invasion, had heavily criticized DeWine for his support of the "stay the course" policy in Iraq.
Brown also campaigned on domestic issues to relieve Ohio's faltering economy; his state has seen job losses in manufacturing and increases in cost of living, while wages have remained flat. His campaign, like those of other Democrats, focused on tax cuts for the middle class.
Soon after the results were announced, Brown thanked supporters in a speech from his headquarters in Columbus.
"This has been a terrific experience today. So many have stood up for the middle class and together we're going to turn around Ohio."