Those who want to eat indoors, enter a theatre or work out inside a gym have to show proof of vaccination.
The mandate means that people will need at least one dose of a coronavirus vaccine to take part in those activities.
It will not be fully enforced until Sept. 13 to give businesses the ability to figure out how to follow the new mandate.
Medical experts in New York City says the odds are against the unvaccinated as the delta variant continues to surge.
The initiative is part of Mayor Bill de Blasio's "Key to NYC Plan" to stop the spread of COVID-19.