Donald Trump vowed to cheering supporters that he would “take back our country” after dominating the Super Tuesday primary contests.
Hours later he became the lone Republican White House contender after rival Nikki Haley dropped out.
President Joe Biden – who largely sailed through the Democratic nominating contests – said Mr Trump was “driven by grievance and grift”.
The results make a repeat of the 2020 US election all but certain.
Both men appear poised to frame the election as an existential test for the future of the country as they head towards a rematch in November.
On Wednesday, Mr Trump made it clear on social media that he had now set his sights on that rematch, challenging Mr Biden to “Debates, ANYTIME, ANYWHERE, ANYPLACE!” on issues that are “so vital to America”.
Polling indicates that many Americans do not want the same choice they had four years ago but the Super Tuesday results make a repeat of 2020 seemingly determined.
Despite the lack of enthusiasm, both men swept nearly all of the contests as voters in 15 states and one territory cast their ballots on the biggest night in the primary calendar.
Mr Trump won in Alabama, Arkansas, California, Colorado, Maine, Massachusetts, Minnesota, North Carolina, Oklahoma, Tennessee, Texas and Virginia.
He lost in Vermont to former UN ambassador Ms Haley, who announced on Wednesday she is quitting the race without endorsing her rival.
Mr Biden swept the same states plus Utah and Vermont, but lost to a Baltimore businessman in the US territory of American Samoa. He also won the Iowa caucus, which announced its results on Tuesday.
His only challenger in the primaries, Dean Phillips, dropped out of the race on Wednesday and endorsed him.
As the two candidates racked up their wins on Super Tuesday, they characterised each other as threats to the US.
Mr Trump warned his supporters at Mar-a-Lago that if “we lose the election, we’re not going to have a country left”.
He invoked one of his key issues, immigration, and the numbers crossing the southern border. He also pledged that the world would see fewer wars if he were president.
Just before Mr Trump spoke, Mr Biden released a statement attacking his opponent.
“Tonight’s results leave the American people with a clear choice,” he said.
“Are we going to keep moving forward or will we allow Donald Trump to drag us backwards into the chaos, division, and darkness that defined his term in office?”