One of the most heated exchanges came when Gingrich lashed out at Mitt Romney, telling the former Massachusetts governor, "The only reason you didn't become a career politician is because you lost to Teddy Kennedy in 1994."
"That's probably true," replied Romney, who lost that Senate contest. He then quipped that if he'd achieved his childhood dream, "I would have been a football star all my life, too."
The debate at Drake University in Des Moines was moderated by ABC News' Diane Sawyer and George Stephanopoulos.
Gingrich defended himself against attacks from Texas Rep. Ron Paul and Minnesota Rep. Michele Bachmann as well as Romney, the former front-runner, in the first debate since he soared to the lead in polls nationally and in Iowa. The state's caucuses on Jan. 3 will kick off the competition for Republican National Convention delegates who will pick an opponent to President Barack Obama.
The six candidates also faced off on a variety of issues including their conservative credentials, family values and job creation.
They were asked for the specific number of jobs they'd create if elected. So far, Romney is the only one to answer, saying he'd generate 11.5 million jobs.
All six Republicans on stage assailed Obama's handling of the economy, the overriding issue of the election, yet split down the middle on legislation making its way toward a year-end vote in Congress to extend a Social Security payroll tax cut into 2012.
Romney, Gingrich and Paul said they favored it. Bachmann, Texas Gov., Rick Perry and former Pennsylvania Sen. Rick Santorum said they opposed the measure.
Gingrich's personal life has become a campaign issue, too, and it came up briefly Saturday night.
Asked whether marital fidelity was a valid concern for voters choosing a candidate, Perry said, "If you cheat on your wife, you'll cheat on your business partner. It's a characteristic people look at."
Gingrich, who has been divorced twice and has admitted past infidelity, said the issue was an important one, then added, "I've made mistakes at times and I've had to go to God for forgiveness."
The Associated Press contributed to this report.