"In the enduring struggle between democracy and tyranny, I know where I stand and I know where the United States belongs," Harris said, accusing Trump of cozying up to dictators.
On the final, and most anticipated, night of the convention, Harris, 59, sought to redefine herself for America as she and Trump enter the final 11 weeks of the razor-close campaign.
After days of protests from Palestinian supporters who were disappointed at not getting a speaking spot at the convention, Harris delivered a pledge to secure Israel, bring the hostages home from Gaza and end the war in the Palestinian enclave.
Watch full speech
"Now is the time to get a hostage deal and a ceasefire deal done," she said to cheers. "And let me be clear, I will always stand up for Israel's right to defend itself and I will always ensure Israel has the ability to defend itself."
"What has happened in Gaza over the past 10 months is devastating. So many innocent lives lost, desperate hungry people fleeing for safety over and over again. The scale of suffering is heartbreaking," she said.
"President Biden and I are working to end this war such that Israel is secure, the hostages are release, the suffering in Gaza ends and the Palestinian people can realize their right to dignity, security, freedom and self-determination."
Harris emerged as the Democratic candidate little more than a month ago when allies of President Joe Biden, 81, forced him to quit the race. If successful, she stands to make history as the first woman elected US president.
She described the November 5 election as a "precious, fleeting opportunity to move past the bitterness, cynicism and divisive battles of the past. A chance to chart a New Way Forward."
Harris drew a series of contrasts with Trump, accusing him of not fighting for the middle class, planning to enact a tax hike through his tariff proposals, and having set into motion the end of a constitutional right to abortion with his picks for the US Supreme Court.
Harris noted the Supreme Court's recent ruling about presidential immunity and the risks that would engender if Trump gained power again.
"Just imagine Donald Trump with no guard rails," she said.
Trump, who had promised to respond to Harris' speech in real time, posted a series of messages on Truth Social as she spoke about him, including: "She stands for Incompetence and Weakness - Our Country is being laughed at all over the World!" and "She will never be respected by the Tyrants of the World!"
Republicans say Democrats have spent more time attacking Trump, who was president from 2017-2021, than elaborating on how they would govern.
NEARLY FOUR YEARS AS VP
A former California attorney general, Harris' presidential ambitions were apparent for years, but they had been undermined by her own shaky 2020 campaign and bumps along the way of her nearly four years as vice president.
Country band The Chicks sang the national anthem, and Pink also performed in the United Center, an arena that seats more than 20,000 people.
The Central Park Five, black men who were exonerated after being wrongly convicted of rape as teenagers and incarcerated for years, got a standing ovation. Members criticised Trump, who as a New York City real estate developer denounced the teenagers at the time. He refused to recant his incorrect claims.
The Democratic crowd went wild for Senator Elizabeth Warren, who grew emotional and wiped away tears. Warren, who made her own White House bid in 2020, delivered a ringing endorsement of Harris as she belittled Trump as "the felon."
Victims of gun violence, including former US Representative Gabby Giffords, also appeared.
Former US Representative Adam Kinzinger, one of the 10 House Republicans who voted to impeach then-President Trump, was one of several Republicans to speak at the convention against Trump.
"Democracy knows no party," Kinzinger said, telling his fellow Republicans that "Democrats are as patriotic as us. They love this country as much as we do."
Over the last three days, Democrats have sought to define themselves as the voice of American values from small towns to overseas.
Harris' forceful stump speeches have been met by a surge in enthusiasm from voters ahead of the election.
She has raised a record-breaking $US500 million ($NZ812 million) in a month and has narrowed the gap or taken the lead against Trump in many opinion polls of battleground states that will decide the vote.
