The US has topped 500,000 deaths from Covid-19, the most for any country in the world.
It comes just over a year after the first infection of the novel coronavirus, first detected in China, was recorded on the US west coast.
The grim milestone will be marked by a candle-lighting ceremony and moment of silence at the White House. President Joe Biden will also deliver remarks.
More than 28.1 million Americans have been infected - another global record.
The figure - currently at 500,071 according to Johns Hopkins University - surpasses the death toll "in a single year of this pandemic [that of] World War I, World War II, and the Vietnam War combined", President Joe Biden said in a White House proclamation remembering the dead.
"On this solemn occasion, we reflect on their loss and on their loved ones left behind. We, as a Nation, must remember them so we can begin to heal, to unite, and find purpose as one Nation to defeat this pandemic," he continued.
The number of Americans who have had the coronavirus is nearly double that of second-highest India (11 million) and Brazil (10.1 million). Brazil has recorded the second-largest death toll at 244,000 while Mexico is in third with 178,000.
"People decades from now are going to be talking about this as a terribly historic milestone in the history of this country, to have these many people to have died from a respiratory-borne infection," the nation's top immunologist, Dr Anthony Fauci, told CNN on Sunday.
At least 90,000 more Americans are expected to be killed by 1 June, according to a recent projection from the University of Washington's Institute for Health Metrics and Evaluation (IHME).
The IHME estimates that by late May, the virus will kill around 500 Americans per day - down from approximately 2,000 daily deaths now.
Hospital admission rates have fallen for 40 straight days, as approximately 1.6 million vaccinations are administered to Americans daily.
Despite the improving figures, Americans' life expectancy has dropped by one full year due to the coronavirus, the US Centers for Disease Control and Prevention said last week. The change has been most acute among racial minorities, who have been disproportionally affected by the deadly virus.
Black men suffered the largest decline, with life expectancy dropping by three years between January and June 2020.
And Hispanic men saw a fall in life expectancy of 2.4 years during that period.