In a contest that pits two politicians viewed as unfavourable by large segments of the American people, Mr Trump will accuse Mrs Clinton of failures while serving as President Barack Obama's first-term secretary of state and cite her use of a private email server and destruction of emails as evidence that "corruption has reached a level like never before".
The acceptance speech by Trump, 70, closed out a four-day convention that underscored his struggle to heal cracks in the Republican Party over his anti-illegal-immigrant rhetoric and concerns about his temperament. The event was boycotted by many big-name establishment Republicans, such as 2012 nominee Mitt Romney and members of the Bush family.
He accused America's first black president of dividing the nation along racial lines.
"I have joined the political arena so that the powerful can no longer beat up on people that cannot defend themselves..."
"Nobody knows the system better than me, which is why I alone can fix it", Trump told a fired-up crowd of backers that packed the downtown Quicken Loans Arena.
The Manhattan mogul sold himself as the champion of a downtrodden working class - "America's blue-collar billionaire" as one speaker had called him earlier in the evening - promising to restore "law and order" and casting himself as a change agent against presumptive Democratic nominee Hillary Clinton.
"When I was a kid, the great debate was about how to defeat the Soviet Union", said Thiel, the co-founder of PayPal and a Trump delegate.
He blasted Clinton for her support of allowing Syrian refugees to enter the country, saying she is "proposing mass amnesty, mass immigration and mass lawlessness".
'After 15 years of wars in the Middle East, after trillions of dollars spent and thousands of lives lost, the situation is worse than it has ever been before.
"This is the legacy of Hillary Clinton: death, destruction and weakness", he said.
Delegate Rey Gonzalez of San Benito said that before the speech, he wanted Trump to convince him that he would unify the party and reach out to people that didn't support him, especially those who backed Cruz. She raved about Trump's message and his delivery: "It's high time we brought in somebody who has a positive attitude about all people".
He also vowed to get tough on criminals, following the recent shootings and attacks that have rocked the country.
Outside the convention hall, Cleveland's Public Square on July 21 attracted hundreds of demonstrators - both supporters and opponents of Trump - amid a sizable police presence. He promised, "the crime and violence that today afflicts our nation will soon, very soon, come to an end".
'Beginning on January 20th 2017, safety will be restored, ' he said. "The GOP convention has shown us that failure is simply not an option".
As Trump moved into the general election campaign, he stuck to the controversial proposals of his primary campaign, including building a wall along the entire U.S.-Mexico border and suspending immigration from nations "compromised by terrorism". The crowd repeatedly broke into chants of "U-S-A!" All those positions go against prevailing Republican beliefs.
Cruz's defiance follows a week of drama, including plagiarism charges against Mr Trump's wife, Melania.
In his one-hour and fourteen minute speech he listed a series of domestic initiatives.
Mr Trump was trailing Mrs Clinton in many opinion polls after a bruising Republican primary season.
Those divisions were laid bare when Trump's last major challenger for the nomination, U.S. Senator Cruz of Texas, urged Republicans to "vote your conscience" and pointedly did not endorse Trump.