Hillary Clinton has called Republican presumptive nominee Donald Trump “dangerously incoherent”.
The Democratic front-runner said Mr Trump was unfit to be president and his election would be a “historic mistake”.
Mr Trump hit back, saying Mrs Clinton “no longer has credibility – too much failure in office”.
Outside Mr Trump’s rally in San Jose, California, anti-Trump protesters clashed with his supporters in one of the worst such confrontations so far.
Several Trump supporters were punched, one was pelted with eggs and others were spat at, reports said.
But in a boost for the presumptive Republican nominee, US House Speaker Republican Paul Ryan said he would back his candidacy.
Mr Ryan had previously refused to back Mr Trump and his support is the latest sign Republicans are unifying around their nominee.
He wrote in a column in his hometown Gazette newspaper in Wisconsin “we have more common ground than disagreement”, and he attacked Mrs Clinton saying: “A Clinton White House would mean four more years of liberal cronyism.”
On the attack
In her speech Mrs Clinton, who is fighting Bernie Sanders for the Democratic nomination, rejected Mr Trump’s foreign policy points, and called him thin-skinned, irrational and unprepared.
She defended the Iran nuclear deal and said a Trump presidency could start overseas wars and ruin the US economy.
“This isn’t reality television, this is actual reality,” she said.
Mrs Clinton also said someone like Mr Trump could not be in charge of the country’s nuclear codes and that his proposals were vague and often nonsensical.
She said his anti-Muslim rhetoric and talk of American isolationism bolstered the so-called Islamic State and argued against his disdain for Mexico and Mexican immigrants coming into the country.
Questioning his relationship with Russian president Vladmir Putin, she said: “I’ll leave it to a psychiatrist to explain his affection for tyrants.”
Mr Sanders has vowed to keep fighting for the nomination until the party’s convention in July, despite Mrs Clinton’s strong delegate lead.