The landmark speech came two months out from the mid-term elections, which will play a key role in deciding how much authority Biden wields over the next two years.
Speaking from Independence Hall in Philadelphia, where the US Declaration of Independence was signed, he picked up his 2020 campaign theme of restoring the "soul of America".
He said: "Not every Republican, not even a majority of Republicans, are MAGA Republicans.
"But there's no question that the Republican Party today is dominated, driven and intimidated by Donald Trump and the MAGA Republicans, and that is a threat to this country."
US President Joe Biden
JONATHAN ERNST
US President Joe Biden with First Lady Jill Biden
JONATHAN ERNST
He continued: "For a long time, we told ourselves that American democracy is guaranteed. But it's not. We have to defend it.
"Protect it. Stand up for it. Each and every one of us."
But Biden's speech did not go down well, as he was heckled and a bullhorn was sounded throughout.
He even addressed the disruption, saying: "They're entitled to be outrageous. This is a democracy."
And his comments sparked backlash from senior Republicans, too.
Kevin McCarthy, minority leader of the House of Representatives, hit back that Mr Biden had "severely wounded America's soul".
The California congressman said the US President "has chosen to divide, demean, and disparage his fellow Americans".
Calling for Biden to apologise, he added: "Why? Simply because they disagree with his policies.
"That is not leadership."
It comes after Biden hit out at the "semi-fascism" he said was on display in fringe Republican groups last week.
