Hundreds of people filled the city streets holding American flags and signs that read: "No to the vaccine, I feel discrimination against, harassed, singled out and rejected for defending my rights."
One anti-vaxxer held two signs that said: "How did the Nazi's (sic) do it? They said the Jews were diseased."
On the other poster, there was a picture of a swastika under text asking, "What happened to 'Never again?!'"
Barely any masks were seen in the crowd and one family used their toddler's stroller to display a sign asking "mask choice".
A pole dancer even took to the streets to perform and protest the vaccine mandate.
Others in the group, which spread for several blocks, refuted vaccine passports and gave out stickers that read: "Those who sell the panic sell the cure."
One woman's poster stated: "my body. My family. My choice. F*** your mandate!"
Saturday's protest comes as the NYC Department of Health said that at least 60 percent of all eligible New York City residents are fully vaccinated.
Since the end of August, the Big Apple now demands proof of vaccination for people attending indoor venues such as restaurants, gyms, and shows, as the city tries to get back on its feet.
The vaccination order intended to convince more people to get vaccinated with the threat of missing out on the city's world-class amenities.
"We do not want to go back to restrictions," De Blasio said at a virtual news conference. "The key to our progress is vaccination."
Businesses had a grace period, which concluded on September 13, to begin executing vaccine checkpoints before facing $1,000 fines.
Mask rules have stayed largely relaxed, although New Yorkers must still practice wearing them on public transport and in health settings, with individual businesses also allowed to impose a mandatory face-covering rule if they wish.
Last month NY Mayor Bill de Blasio said every department of education employee must receive at least one dose of a coronavirus vaccine by September 27 to prevent the hyper-contagious Delta variant from spreading through the city.
He did not offer the option of a weekly test instead.
Information from the city revealed that only 28 percent of black NYC residents between the ages of 18 and 44 are fully vaccinated, compared to 49 percent of Hispanics, 52 percent of whites, and 82 percent of Asians in the same age group.