Djokovic has already missed one grand slam this year, with the 21-time major champion absent from the Australian Open after a protracted saga surrounding his visa ended with him being deported on public health grounds.
The Serbian was permitted to play at the French Open and Wimbledon, winning the latter for the seventh time in his career, despite being unvaccinated against COVID-19.
However, he is unlikely to have a chance to compete for a fourth singles title at Flushing Meadows.
Djokovic was included on the entry list for the final slam of 2022, but the U.S. government does not permit unvaccinated non-U.S citizens to enter the country.
In a statement released alongside the entry lists, the USTA said: "Per the ITF Grand Slam rulebook, all eligible players are automatically entered into the men's and women's singles main-draw fields based on ranking 42 days prior to the first Monday of the event.
"The US Open does not have a vaccination mandate in place for players, but it will respect the U.S. government's position regarding travel into the country for unvaccinated non-U.S. citizens."
Should Djokovic miss the New York major, it will mean he will not get the chance to play in a grand slam until the 2023 French Open.
Having had his visa to enter Australia cancelled, Djokovic is banned from re-applying for three years. Unless that ban is reversed or reduced, the 35-year-old may well have played his final Australian Open.
Djokovic is one major title shy of Rafael Nadal's record of 22 following his four-set win over Nick Kyrgios in the Wimbledon final.
He reached the final of last year's US Open but lost to Daniil Medvedev in straight sets, preventing him from claiming the calendar Grand Slam.
A month later, the White House issued a presidential proclamation declaring that non-U.S. citizens must be vaccinated to enter the country, effectively ending his hopes of going one better in 2022.