The presidential frontrunner parried jabs by Vermont senator Bernie Sanders and three other party hopefuls, who challenged her on everything from political flip-flops to gun control and military intervention in the Middle East.
But the former secretary of state - who took part in more than 20 debates in the 2008 White House race - appeared mostly polished and composed during the two-hour clash in Las Vegas.
"She was pretty unflappable. Nobody got under her skin," University of Iowa political science professor Timothy Hagle told AFP.
Clinton's head of communications Jennifer Palmieri was upbeat after the debate, saying: "She did well tonight. She should feel good".
The debate saw a few fiery moments too, with Clinton accusing Sanders - her chief rival for the Democratic nomination - of being soft on gun control.
But Clinton received surprise respite from attacks over her use of a private email server as US top diplomat - seen as an Achilles Heel - with Sanders and others coming to her defense.
"Enough of the e-mails! The American people are sick and tired of hearing about your damn e-mails," Sanders fumed.
Overall, though, the debate was spared the dramatic clashes of personalities seen in the first two Republican debates, dominated by the figure of Donald Trump.
The real estate mogul live-tweeted the event, needling the candidates even before they took to the lecterns.
"Sorry, there is no STAR on the stage tonight!" wrote the @realDonaldTrump.
The 67-year-old Clinton was keen to inject excitement into her campaign and show she can rally the Democratic base, while Sanders was testing whether his "political revolution" can translate to the national stage.
Sanders put forward passionate arguments for reducing income inequality, insisting he was not a part of the "casino capitalist" system.
"I believe in a society where all people do well, not just Wall Street billionaires," he said.
Keen to reinforce her liberal bona fides, Clinton said "I don't take a backseat to anyone" when it comes to progressive policies.
But when Sanders pointed to Nordic countries as an example for America, Clinton put her foot down.
"We are not Denmark. I love Denmark. We are the United States of America," she said.
Nearly eight years after her primary campaign clashes with Barack Obama, Clinton displayed strong command of the issues and kept her rivals at bay.
Asked pointedly by the CNN moderator, regarding her changes in policy positions, if she would say anything to get elected, she replied: "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 said.
Clinton's rivals parted ways her on key policy areas.On Syria, where she supports a no-fly zone, Sanders warned greater intervention could lead to boots on the ground.
"When you talk about Syria, you're talking about a quagmire in a quagmire," said Sanders.
And Lincoln Chafee, one of the three longshot hopefuls on the stage, blasted Clinton for her "poor judgment calls" in voting as senator to authorize the use of force in Iraq - which she has acknowledged was a "mistake".
But former Rhode Island governor Chafee, former Maryland governor Martin O'Malley, and ex-Virginia senator Jim Webb all struggled to generate breakout moments in a debate dominated by Clinton and Sanders.
For 74-year-old Sanders, a rumpled, self-declared democratic socialist, Tuesday was the biggest test of his decades-long political career.
Clinton used her rival's moderate position on guns - Sanders hails from Vermont, a rural state with few firearm restrictions - to highlight an area where liberals who seek tighter gun laws break with Sanders.
Asked if Sanders was tough enough on the gun issue, a steely Clinton said "No, not at all".
The election is nearly 13 months away, but in February Americans begin the months-long voting process of selecting their party nominees.
Clinton still leads nationally, but she trails Sanders by nearly 10 points in New Hampshire and holds only a modest lead in Iowa.
Both are key early-voting states in the nomination process, setting momentum for the rest of the primary race.
Asked as the debate was winding up how her presidency would differ from Obama's, Clinton offered the quickfire response: "Well, I think that's pretty obvious. I think being the first woman president would be quite a change."
Bill Clinton himself was not present for the debate, but he delivered a boost via Twitter, saying: "I'm proud of @HillaryClinton. Tonight, she showed why she should be President."
Key moments
• 'Will you say anything to get elected?' - CNN moderator Anderson Cooper opened the debate with a tough question for Clinton about policy flip-flops and what she is willing to do to gain power, a topic that has dogged the former first lady, secretary of State and New York senator."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," Clinton shot back, with a steel that would be seen throughout the evening.
• Barnstorming Bernie - Bernie Sanders, Clinton's nearest rival in the polls, wasted no time in displaying his leftist chops, speaking in a tone that for America's conventional politics sounded uncompromising, bordering on revolutionary.
"Do I consider myself part of the casino capitalist process by which so few have so much and so many have so little, by which Wall Street's greed and recklessness wrecked this economy? No, I don't," he said. "I believe in a society where all people do well. Not just a handful of billionaires."
• 'We are not Denmark' - On economics and on social issues, Clinton sought to draw sharp contrasts between Sanders's movement politics and her own more centrist appeal.
"We are not Denmark," Clinton told her rival, who had praised the so-called "Nordic model" of social inclusion.
She did, however, concede it was sometimes necessary to "save capitalism from itself".
Clinton criticized Sanders for not being tough enough on gun control.
"As a senator from a rural state, what I can tell secretary Clinton (is) that all the shouting in the world is not going to do what I would hope all of us want," said the Vermont lawmaker.
• Enough of the emails - Clinton did manage to enlist Sanders's help in parrying questions about her use of a private email server while secretary of State.
"Enough of the emails!" said an exasperated Sanders, addressing the moderator and turning to Clinton.
"The American people are sick and tired of hearing about your damn emails.
"Thank you. Me too. Me too," she replied.
• Main enemy - With oodles more fundraising ahead and the party base needing to be fired up, the Democratic contenders reveled in listing their chief political enemies, familiar Democratic foils ranging from the National Rifle Association to Wall Street to the pharmaceutical industry.
Clinton got perhaps the largest cheers for her list that spoke to a lifetime in the cauldron of partisan Washington: "In addition to the NRA, the health insurance companies, the drug companies, the Iranians, probably the Republicans," she said with a smile.
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