The attacks turned personal as the Republican accused Democratic candidate Hillary Clinton of not having the right temperament to be president.
Meanwhile, Hillary Clinton baited Donald Trump by pointing out that he refuses to release his tax returns.
The first presidential debate in New York could be the most watched debate in TV history, with up to 100 million viewers.
Hours before the CNN program, polls suggested the candidates were locked in a dead heat, adding to the tension between the rivals on stage throughout the debate.
“I have a feeling that by the end of this evening, I’m going to be blamed for everything that’s ever happened,” Hillary Clinton quipped when prompted to respond to one of Donald Trump’s attacks.
“Why not?” Donald Trump interrupted.
“Yeah, why not,” Hillary Clinton answered.
“You know, just join the debate by saying more crazy things.”
Donald Trump was later thrown on the defensive by moderator Lester Holt for not disclosing his tax returns.
The billionaire claimed he was under a “routine audit” and would release the document once the audit was finished.
However, Donald Trump promised he would release them if Hillary Clinton released 33,000 emails that were deleted during an investigation into her private email set-up while secretary of state.
Hillary Clinton made a brief response to Donald Trump’s attacks about her use of a private email server – which has haunted her on the campaign trail.
She said there were no excuses for the “mistake” and that she takes responsibility for it.
Hillary Clinton was also uncomfortable when defending her changing position on the controversial Trans-Pacific Partnership trade deal.
One key exchange was over Donald Trump’s long-held belief that President Barack Obama was born outside the United States, a position he finally reversed two weeks ago.
“He has a long record of engaging in racist behavior,” Hillary Clinton said, adding that it was a “very hurtful” lie that annoyed and bothered the first African American president.
When asked by Lester Holt to explain his change in stance, Donald Trump said he wanted to concentrate on bigger, more important issues.
Hillary Clinton attacked Donald Trump for praising Russian President Vladimir Putin, and suggesting he “find” her emails.
“I was so shocked when Donald publicly invited Putin to hack into Americans. That is just unacceptable… Donald is unfit to be commander-in-chief.”
The September 26 debate was the first of three between the two candidates.
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