Deterring a Nice-style truck attack against Thursday’s Thanksgiving Day Parade has led the NYPD — for the first time in recent memory — to ban vehicles from crossing the route, NYPD and city officials said at news conference late Wednesday afternoon as handlers inflated balloons nearby for the 90th procession.

In past Thanksgiving Day parades, vehicles were periodically allowed to pass cross town, usually at 57th and 42nd streets, during lulls in the nearly 50-block holiday staple.

That changes Thursday. Instead, said NYPD Commissioner James O’Neill, drivers will have to “figure it out” and find another route.

“I’m worried about keeping everyone safe,” O’Neill said at the news conference at 77th Street and Central Park West, not far from where the parade starts. The ban was expected to begin at 10 p.m. Wednesday and continue through about noon Thursday.

Despite a recent article in an ISIS online magazine that called the parade an “excellent target” for attack, Mayor Bill de Blasio said it wouldn’t dissuade throngs of viewers expected to lined the route Thursday morning like they did last year when an estimated crowd of 3.5 million turned out.

“Not in New York, pal,” de Blasio said as he stood in the shadow of a giant Charlie Brown balloon.

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The mayor said that while there are no specific threats against the parade, the NYPD is ready for anything, based on intelligence gathered by department detectives who have visited attack scenes around the world.

“New Yorkers are very clear that no matter what is going on around us, we are always New York,” de Blasio said. “We remain true to our values. New Yorkers are strong and resilient.”

To protect the crowd, nearly 100 sand-filled trucks will block crosstown traffic. “Vapor wake” dogs capable of tracking an explosive through crowds, and more than 3,000 cops will be deployed on the parade route and surrounding streets.

Heavily armed officers will also line the parade.

The NYPD’s chief spokesman, Steve Davis, said the new crosstown vehicle prohibition could be expanded to other parades.

“We’re gonna play it by ear,” Davis said.

The beefed up security comes as officials remain mindful of the ISIS article, the Bastille Day attack in France, and other past terrorism threats globally.

The July 14 terrorist act in Nice killed nearly 90 people when a 31-year-old Tunisian man living in France intentionally drove a truck into a festive crowd.

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The driver, a lone-wolf attacker French officials said was inspired by ISIS, also died in the bombing.

After the attack, NYPD officials studied and learned from it and tweaked security measures for large city events like the Thanksgiving Day parade.

Thursday’s version snakes south from its start between 77th Street and Central Park West, turns left onto Central Park South at Columbus Circle, makes a right turn on 6th Avenue and continues south until it ends on 34th Street in Herald Square.

According to parade organizers, there are nearly 40 balloons and more than two dozen floats this year, as well as 1,100 cheerleaders and dancers set to take part. Wednesday night, a crowd estimated by parade organizers to be in the hundreds of thousands descended on the area near Central Park and the Museum of National History to watch the balloons being inflated.

Traffic restrictions expected to begin at 10 p.m. Wednesday night.