Ryan repeatedly sought to focus the debate on the Obama-Biden record of the last four years, arguing the administration's policies hindered economic recovery and weakened the nation's standing and influence in the world.
For his part, Biden tried to frame the election as a choice between differing directions for the country by contending policies of the Romney-Ryan ticket would hurt the middle class and move the nation backward on social issues such as gay rights and abortion.
Martha Raddatz of ABC News aggressively moderated the debate, challenging both candidates on some claims and moving on to various topics covering both domestic and foreign policy.
Unlike Obama last week, Biden made sure to mention Romney's controversial comments secretly recorded at a May fundraiser in which the former Massachusetts governor spoke of 47% of Americans who depend on government benefits and won't vote Republican.
"Romney points out 47% of the people won't take responsibility," Biden said. "... He's talking about the people that have built this country. All they're looking for is an even shot."
In the biggest laugh line of the night, Ryan conceded Romney didn't express the thought exactly as he wanted at the fundraiser, then needled the gaffe-prone Biden by saying: "I think the vice president very well knows that sometimes the words don't come out of your mouth the right way." Biden immediately responded "but I always say what I mean," later adding that if anyone thought Romney's "little soliloquy on the 47%" was just a misstatement, "then I think you're ... I've got a bridge to sell you."
Ryan, the conservative congressman from Wisconsin, criticized Obama's administration for its failure to protect four Americans killed in the Libya attack last month, and for mixed messages about what transpired.
"This Benghazi issue would be a tragedy in and of itself. But unfortunately it's indicative of a larger problem," Ryan said, adding that illustrated an unraveling of the administration's foreign policy.
Biden smiled and shook his head as Ryan delivered his criticism, then responded that "not a single thing he said was accurate."
On Iran, widely backed international sanctions pushed by Obama and backed by allies have devastated the Tehran economy, Biden said. He rejected assertions that Obama failed to work closely with Israeli Prime Minister Benjamin Netanyahu, and that the United States lacked commitment to a possible military strike to prevent Iran from becoming capable of developing a nuclear weapon.
"This president doesn't bluff," Biden said.
Ryan, however, insisted that Iran was closer now to having a nuclear weapon than it was four years ago, blaming the administration for allowing that to happen. He bluntly said that Tehran must not be allowed to become a nuclear power.
"This is the world's largest sponsor of terrorism," he said. "And if they get nuclear weapons, other people in the neighborhood will pursue nuclear weapons as well. We can't live with that."
Last week, Obama was chided for being passive, and polls conducted after the debate indicate the White House race is now extremely tight ahead of the election.
Key surveys indicate that Obama and Romney are knotted up in the battleground states of Virginia, Florida, Ohio, Wisconsin and Colorado. Most experts believe that nine swing states will determine the next president.