4,076 deaths – more than twice the 2,010 recorded on Saturday – were reported.
The number eclipsed the official count of 3,305 victims in China, putting the US only behind Italy and Spain for recording more deaths from the disease to date.
The number of confirmed US cases is now higher than anywhere in the world, having reached 189,510.
With the US death toll doubling every three days, president Donald Trump warned on Tuesday that Americans needed to brace for a “very, very painful two weeks”.
White House projections indicate that the coronavirus could cause anywhere between 100,000 to 240,000 deaths, even with existing social distancing measures still in place.
“I want every American to be prepared for the hard days that lie ahead,” Mr Trump told reporters at the latest press briefing.
More Americans have now died from the Covid-19 virus than those from the 9/11 terror attacks on New York City.
On Wednesday, Manhattan had recorded more than 900 deaths in the borough alone, as US military personnel erected temporary hospitals across the city.
According to data provided by John Hopkins University, more than 40 per cent of all US coronavirus deaths so far have come from New York state where there have been over 1,700 confirmed deaths.
Dr Birx, the White House coronavirus response coordinator, said that the states of New York and New Jersey together had more cumulative cases then the other 48 states combined.
New York, the epicentre of the nation’s outbreak, had so far seen 76,000 confirmed cases of the virus.
The president’s sombre performance at Tuesday’s briefing came after he extended nation-wide social distancing measures to April 30 on Sunday.
He also claimed that his previous ambition to reopen the US economy and ease the shutdown before Easter was “aspirational”.
Globally, more than 858,000 people have tested positive for the coronavirus and over 42,100 people have died.