Mack attacked Nelson on his voting record, saying that the Democrat has stood with President Barack Obama 98 percent of the time instead of standing with the people of the Sunshine State.
For his part, Nelson accused Mack of having one of the worst attendance records in Congress, saying he has missed 178 votes this year.
In their only debate before the Nov. 6 election, the candidates disagreed on a host of partisan issues from health care reform to government spending.
They were also at loggerheads over Nelson's budget and Medicare votes.
Mack said that Nelson, on the budget committee, has failed to pass a budget in four years. The Democrat replied that a budget was passed last year.
“Apparently you don’t understand that we have failed to pass a budget," Mack said.
“Check the record. It’s the Budget Control Act," replied Nelson, who is seeking a third term.
Mack also accused Nelson of voting to raise taxes 150 times and casting the deciding vote on President Barack Obama's health care overhaul, while Nelson said the Republican nominee is distorting his record.
Wednesday's debate was held at Nova Southeastern University in Davie. It was organized by Leadership Florida and the Florida Press Association.
The candidates also discussed immigration reform, national security and the American embargo on Cuba.
“No, we should not lift the embargo. We clearly should allow family members to travel and to take remittances, and that has been expanded, but not to lift the embargo," Nelson said.
Mack actually agreed with Nelson on the embargo question – while taking a jab at his opponent.
"We should not lift the embargo to help fund someone who wants to hurt his own people. Now, Senator Nelson has voted to weaken restrictions, which then helps the Castro regime," he said.
They concurred on little else.
"Senator, you keep talking about my record. I think you must have been looking somebody else up," Mack said at one point.
"There you go again," Nelson responded.
The debate came as hundreds of thousands of people have already cast their votes with absentee ballots.
The race could have implications on the balance of power in the Senate. Republicans need to gain four seats to have a majority. Outside groups supporting both sides have spent millions of dollars trying to influence the Florida race.