The debate was seen as critical for Harris, the former secretary of state who oversaw the Florida recount in 2000 that put President Bush into office. She has consistently trailed in the polls and lacks the money to run statewide TV commercials before Election Day.
Moderator Tim Russert pressured her to say whether she would vote for the war in Iraq now knowing that Iraq did not have the weapons of mass destruction. She repeatedly declined to answer.
Instead, she said, "If we knew today what we knew back then, there never would have been a vote called to go to war."
Nelson, the incumbent senator, said he would have voted against the war.
"The word is not mistake, the word is misrepresentation," Nelson said of what lawmakers were told about weapons in Iraq. "We were given the wrong information. We were given massaged information."
On taxes, Harris attacked Nelson as a liberal who would raise them. Nelson, meanwhile, said he voted against President Bush's initial tax cut bill because it was flawed but has voted 81 times to cut taxes or extend tax cuts.
Harris also criticized Democrats for not offering solutions to protect Social Security. Nelson accused her of making it a partisan issue.
"Listen to the words of my opponent — the Democrats this, the Democrats that," he said. "The only way we can solve these kinds of problems and lot of the other problems, including Iraq, is to reach out to both sides of the aisle and bring people together."
Harris, 49, gained the adoration of the Republican rank-and-file — and the scorn of Democrats — during the 2000 recount. She won her congressional seat in 2002 and was re-elected in 2004.
Support for her campaign was lacking initially from state GOP leaders, including Gov. Jeb Bush, who tried to recruit someone else to run. Campaign workers have defected in droves and she has had to answer questions about her dealings with a corrupt defense contractor.
An Oct. 25 poll from Quinnipiac University showed Nelson was favored by 64 percent of likely voters, compared to 29 percent for Harris. The poll has a sampling error margin of plus or minus three percentage points.
When asked by reporters afterward if she was able to close the gap between her and Nelson, Harris said, "You know, I can't speculate. I just hope that I reached out to the hearts and minds of people. The people of Florida need to know that I care about them."