In a performance aimed at solidifying her lock on the Democratic nomination, Clinton sought to pivot from a tough summer in which the controversy over her private email server triggered a slump in popularity ratings. She proved to be a polished debater, showing little rust after enduring 25 debates during the 2008 campaign.
The former secretary of state dominated the opening exchanges, parrying questions on the depth of her political convictions and insisting she is a "progressive" despite the doubts of some on the left of the party.
"I have been very consistent," Clinton said. "Over the course of my entire life, I have always fought for the same values and principles, but, like most human beings, including those of us who run for office, I do absorb new information. I do look at what's happening in the world."
She quickly took shots at progressive challenger Sanders, first for his political philosophy.
Sanders defended his self-identified status as a democratic socialist, which many commentators believe frames him as far too left-wing to be able to win a general election. He said he wanted no part of the "casino capitalism" economy and railed against a system where the top 10% in the country have more wealth than the bottom 90%.
He went on to argue that his vision for politics was akin to Scandinavian nations with strong health care systems and social safety nets.
Clinton replied, "I love Denmark!" but argued that they were running for president of the United States of America and such economic policies would not work here.
The former secretary of state also slammed Sanders for his positions on guns, including voting against legislation such as the Brady Bill. Clinton was asked whether Sanders had been tough enough on regulating firearms.
"No, not at all," Clinton said. "This has gone on too long and it is time the entire country stand up against the NRA."
But Sanders hit back, telling Clinton sharply that "all the shouting in the world is not going to do what I hope all of us want," namely more restrictions on firearms.
Despite the heated back-and-forth, Sanders came to Clinton's defense on the email saga from her stint as secretary of state.
"The American people are sick and tired of hearing about your damn emails," Sanders said to applause that was followed by a handshake between Clinton and the senator.
The White House hopefuls were in Las Vegas at the Wynn hotel and casino for one of just six Democratic debates slated before the party chooses a nominee.
Sanders sought to appeal to a wider audience of Democrats beyond those who have flocked in the thousands to his events in early-voting states such as Iowa, where he is polling just behind Clinton, and in New Hampshire, where he is leading in several surveys.
Clinton holds a commanding lead nationally despite Sanders' strong performance in the early states.
Three other candidates -- former Rhode Island Gov. Lincoln Chafee, former Virginia Sen. Jim Webb and former Maryland Gov. Martin O'Malley -- were on stage with Clinton and Sanders. Their campaigns are languishing in the single digits so they tried to use the debate to create much needed buzz.
In his opening statement, Chafee seemed to take a clear shot at Clinton and her struggles to overcome the email controversy, saying that in all his years of public service, he had shown "high ethical standards" and had not been involved in any scandals.
O'Malley warned of a deep crisis of "economic injustice that threatens to tear our country apart."
The candidates also differed on foreign policy.
Clinton defended her role in engineering a "reset" of relations with Russia while secretary of state and said things had changed only when Vladimir Putin returned to the presidency. She said the United States must stand up to Putin's "bullying" and must take "more of a leadership position" to help end the bloody civil war in Syria.
That prompted Sanders to slam the war as a "quagmire in a quagmire" and argued that it was triggered by the war in Iraq -- a clear reference to Clinton's decision as a New York senator to authorize the war in Iraq in late 2002.
Seeking to prevent yet another presidential election being consumed by a debate over that fateful vote, Clinton invoked President Barack Obama to defend herself.
"After the election (in 2008) he asked me to become secretary of state. He valued my judgment and I spent a lot of time with him in the Situation Room going over some very difficult issues."
Both Sanders and O'Malley hit Clinton over her call for a no-fly zone in Syria, with the former Maryland governor warning it could cause a clash with Russian forces operating over the war-torn Middle Eastern nation and that as president, he would be less likely to use a "military tool" than she would be.
Clinton reminded O'Malley that he endorsed her for president in 2008.
Republicans have already held two fiery debates dominated by the presence of Donald Trump.
Trump was live-tweeting during what he predicted would be a "very boring" debate, which could create an unwelcome distraction for candidates trying to get their message out.
He started tweeting before the debate even began, bemoaning the fact that three lower-polling candidates will get so much time.
"But who knows, maybe a star will be born (unlikely)," he wrote. "We will all have fun and hopefully learn something tonight. I will shoot straight and call it as I see it, both the good and the bad. Enjoy!"
In an election that has elevated politicians seen as outsiders and non-politicians, Clinton sought to play up her own historic status.
"I can't think anything more outsider than electing the first woman president."
She also took aim at the perception that electing her would perpetuate the kind of dynastic politics that many Americans dislike.
"I would not ask anyone to vote for me based on my last name," she said. "I am certainly not campaigning to become president because my last name is Clinton. I am campaigning because I think I have the right combination of what the country needs at this point and I think I can take the fight to the Republicans because we cannot afford a Republican to succeed Barack Obama as president of the United States."
The candidates were behind five debate podiums -- but there could have been six.
Vice President Joe Biden is still agonizing over whether to jump into the race even at this late stage and spent the weekend going over his options with his family in Delaware. But he didn't announce a decision in time to join the debate.
Sanders was joined at the debate by his wife, Jane, and two of his children, Levy and David.
Former President Bill Clinton planned to watch his wife's performance on television, though he did arrive in Las Vegas on Monday with the former secretary of state.
And in a reminder of the stakes facing Democrats desperate to hold the White House, the crowd was shown a taped message from Obama before the debate began.
The President recalled the hard-fought primary in 2008, and the video highlighted his legacy, including health care reform and the push for same-sex marriage.
"We are going to have to fight just as hard in this election, as we did in the last two ... that is why I am still fired up and I am still ready to go," Obama said, repeating a 2008 campaign mantra.