Though Trump has not formally secured the 1,237 delegates he needs to win the nomination -- and likely won't until June -- there is no serious opposition left to block his path.
His victory amounts to a stunning takeover of the Republican Party by a candidate with no political experience. Along the way, he eviscerated the GOP's most accomplished presidential field in a generation and captured the Zeitgeist of a party in which grass roots voters harbor deep ill will toward establishment elites.
"It is a beautiful thing to watch, and a beautiful thing to behold," Trump said during a victory speech. "We are going to make America great again."
Cruz tried everything to pull off a last-ditch win in Indiana, including the unusual move of selecting Carly Fiorina as his running mate even though he wasn't the nominee. He also forged a pact with John Kasich that would allow him to focus on Indiana while the Ohio governor would devote his time to later states.
But none of the moves worked.
"We left it all on the field in Indiana. We gave it everything we've got but the voters chose another path," Cruz said. "So with a heavy heart but with boundless optimism for the long-term future of our nation, we are suspending our campaign."
With 97% of the vote in at nearly 12 a.m. ET, Trump was in the lead with 53.2% while Cruz was at 36.7%. Kasich was at 7.6%.
Following Cruz's speech, Republican National Committee Chairman Reince Priebus tweeted Trump is now the presumptive nominee and encouraged the party to "unite and focus on defeating" Hillary Clinton.
Trump paid tribute to Cruz in an effort to bring the party together.
"He is one tough competitor," Trump said. "He is a smart tough guy."
Trump quickly turned his fire on Clinton, saying she would be a "poor president." He also said she "doesn't understand trade" and lashed out at the "deep carnage" he said had been wrought by the North American Free Trade Agreement that was ratified during the presidency of her husband, Bill Clinton.
But the Clinton camp quickly hit back, signaling that with Trump's ascension to presumptive nominee status, the tone of the 2016 race has changed.
Campaign chairman John Podesta issued a statement saying that Trump would be a "risky choice" for president, saying he was neither prepared to keep Americans safe nor to help working families get ahead. "Donald Trump has demonstrated that he's too divisive and lacks the temperament to lead our nation and the free world," Podesta said.
"While Donald Trump seeks to bully and divide Americans, Hillary Clinton will unite us to create an economy that works for everyone."
Galvanizing the GOP
Trump's candidacy has galvanized the GOP, bringing in voters -- especially in regions like the Rust Belt -- that might not otherwise be attracted to the party's message. In the process, he's toppled a GOP field that, at the start, included many well-respected governors and senators.
GOP elites now face the long-feared reality of Trump as an outsider nominee who will lead them into the fall campaign after splitting the party, overturning establishment and conservative power bases and alienating key general election voters with incendiary rhetoric.
The anti-Trump movement said it would fight on as Trump was still short of the delegates needed to secure the nomination. Katie Packer, the chair of Our Principles PAC, said there is still time for Trump to "continue to disqualify himself in the eyes of voters."
"We continue to give voice to the belief of so many Republicans that Trump is not a conservative, does not represent the values of the Republican Party, cannot beat Hillary Clinton, and is simply unfit to be President of the United States," she said in a statement.
For his part, Kasich insisted he would remain in the race.
"Tonight's results are not going to alter Gov. Kasich's campaign plans," said John Weaver, Kasich's chief strategist. "Our strategy has been and continues to be one that involves winning the nomination at an open convention."
By 9:30 p.m. ET, Trump picked up 51 delegates from Indiana, bringing him to 1,053. Cruz had 572.
Sanders wins Indiana
Meanwhile, Bernie Sanders won the Indiana Democratic primary, a victory that will boost his campaign's morale but do little to cut deeply into Clinton's lead of nearly 300 pledged delegates. With 93% of the vote counted, Sanders had won 42 pledged delegates in Indiana and Clinton will win 36. Seven superdelegates in the state have already declared for Clinton.
But Sanders vowed to fight on, even though he admitted that the path he had was a "narrow" one and relied on convincing Democratic superdelegates -- party officials and lawmakers -- to back him and not Clinton.
"The Clinton campaign, a lot of the media, had decided the campaign was over," Sanders told CNN's Jake Tapper in an interview. "Apparently, the people of Indiana did not quite agree with that," Sanders said.
Sanders said he had "a shot" to win upcoming primaries in West Virginia, Oregon and Kentucky and argued his new momentum means that even if Clinton's victory is now seen by many Democrats as inevitable, she is hardly enjoying the triumphant march to the finish line that she hoped for.
Sanders also challenged Clinton, who would prefer to be turning her attention to Trump, to agree to a debate in California before the state's delegate-rich primary on June 7.
But the main focus of Tuesday night was the Republican race -- and a remarkable change of mood from Trump's camp after a day in which he and Cruz had swapped some of their most vehement attacks of the campaign.
Cruz, facing the prospect of an Indiana defeat, snapped after weeks of personal attacks from Trump that included fresh insinuations that his father was associated with Lee Harvey Oswald.
"I'm going to tell you what I really think of Donald Trump," he told reporters at a morning news conference.
Cruz blasted Trump as a "pathological liar," "utterly amoral," "a narcissist at a level I don't think this country's ever seen" and "a serial philanderer."
He unleashed his full arsenal of insults in his attack on Trump.
"He is proud of being a serial philanderer ... he describes his own battles with venereal diseases as his own personal Vietnam," Cruz said, citing a decades-old Trump appearance on "The Howard Stern Show."
"This man is a pathological liar, he doesn't know the difference between truth and lies ... in a pattern that is straight out of a psychology textbook, he accuses everyone of lying," Cruz said as Indiana voters headed to cast their ballots. "Whatever lie he's telling, at that minute he believes it ... the man is utterly immoral," Cruz said.
Trump hit back in a statement blasting Cruz as a "desperate candidate trying to save his failing campaign."
The volley reflected the increasingly personal battle between Cruz and Trump in the final days of the Indiana contest. Earlier Tuesday, Trump had criticized Rafael Cruz, the senator's father, calling him "disgraceful" after he urged evangelical voters in Indiana to reject his son's rival.
Trump also referenced a report from the tabloid National Enquirer -- without naming the publication -- which alleged that it had identified Rafael Cruz in a photo with Lee Harvey Oswald months prior to the JFK assassination. CNN has not independently confirmed that report -- and there is no evidence that it is true.
"And (Ted Cruz's) father, you know, was with Lee Harvey Oswald prior to Oswald's, you know, being shot. I mean the whole thing is ridiculous," Trump said in an interview on "Fox and Friends." "I mean what was he doing with Lee Harvey Oswald, shortly before the death? Before the shooting? It's horrible."