"We're in a tough stretch, and it could last for a while," Biden said in White House remarks. But, he added: "We can and we will turn the tide on COVID-19."
Before discussing the new plan, Biden had sharp words for eligible unvaccinated Americans and officials trying to fight public health mandates.
"Many of us are frustrated with the nearly 80 million Americans who are still not vaccinated," he said, adding later: "We've been patient but our patience is running thin."
The Department of Labor's Occupational Safety and Health Administration will formally issue the rule in coming weeks, a senior administration official told reporters. The rule would apply to more than 80 million workers, Biden said.
Biden also announced that employers meeting the 100 worker threshold must give employees paid time off to get themselves or family members vaccinated.
"No one should lose pay in order to get vaccinated or take a loved one to get vaccinated," he said.
The announcement is part of what the White House calls a new six-pronged strategy to contain the delta variant of the coronavirus as confirmed cases continue to surge across the country.
The vaccine mandate rule coming from the federal government, as opposed to being individually enforced, will shield employers from facing the brunt of potential blowback, said employment lawyer Brett Coburn of firm Alston & Bird.
"I'm sure there will be a lot of employers who chafe at this for a variety of reasons, but some employers I think may welcome it," he said. "It kind of takes it out of their hands to some extent to say, 'Sorry, OSHA said we have to do this and we have to follow what OSHA tells us.'
"The CDC gives us guidelines. OSHA gives us rules. And that's a really important distinction," Coburn said, noting that he has seen a growing number of companies in the last month move toward vaccine requirements.