Never underestimate your friendly neighborhood Spider-Man, even with a mutating virus afoot.

Despite rising concerns over the omicron variant, "Spider-Man: No Way Home" not only shattered pandemic-era box office records; it became the third-best opening of all time behind "Avengers: Endgame" ($357.1 million) and "Avengers: Infinity War" ($257.7 million).

The Sony and Marvel blockbuster grossed a stunning $253 million in ticket sales from 4,325 North American locations, according to studio estimates on Sunday, also setting a record for the month of December.

The web-slinger's success couldn't have come sooner for a movie business that has had a roller coaster 2021 and could be headed for a difficult start to 2022 as the omicron variant of the coronavirus forces more and more event cancellations.

In its five days playing in theaters internationally, it's amassed $334.2 million in ticket sales, bringing its global total to $587.2 million against a $200 million production budget.

The film has yet to open in markets like Thailand and Japan, and there is no release date set for China.

As the third standalone Spider-Man film in the Tom Holland era, "No Way Home" was always going to be an "event film" for fans.

After several delays over the year, Sony planted its launch in the pre-Christmas frame and as of late last week had anticipated a pandemic-best opening in the $130 million to $150 million range.

But it quickly became clear that "Spider-Man" was going to fly much higher. The film netted an incredible $121.5 million in its first day — bumping "Star Wars: The Force Awakens" out of the No. 2 position.

And it's not just fans who have been giving the film good marks: Reviews have been overwhelmingly positive as well.

It has a 94% "fresh" rating on Rotten Tomatoes.

"Spider-Man" could also help the industry at large as it heads into 2022.

Dave Briggs and Alex Livingston from Newsy along with the Associated Press contributed to this story.

Tickets for "Spider-Man: No Way Home" overloaded ticket sites Monday. That's great news for the box office.

Fans complained on social media Monday that ticket sites such as AMC were backed up. This delayed them from getting advance tickets to the newest film featuring the web-slinging hero, which hits theaters on Dec. 17.

The demand is a good sign for cineplexes, which could use a major blockbuster to end 2021 on high note after yet another challenging pandemic year. More importantly, after months of films slowly returning to theaters, a big hit could build momentum further into 2022.

While 2021 produced several comparative successes — including "Shang-Chi and the Legend of the Ten Rings," "F9: The Fast Saga" and Venom: Let There Be Carnage" — those films were blockbusters of the pandemic era, and could have been bigger if not for the health crisis. Ticket sales were constrained by pandemic restrictions and moviegoers' slow return to theaters.

But now "No Way Home," which is being released by Sony, could more closely resemble a blockbuster from the pre-pandemic era. The film is set to be the biggest moneymaker of 2021, and it could be the first of the year to open to $100 million domestically.

Big pre-pandemic films such as 2019's "Avengers: Endgame" and the new Star Wars films of the last decade also overloaded theater sites when tickets first went on sale — and those films went on to break box office records. Sony and theater operators are hoping "No Way Home" can do the same.

So why is there so much anticipation around the movie? Spider-Man has been one of the most reliable brands at the ticket booth: The title role, which has been played by multiple actors over the years, has anchored films that have made more than $6.3 billion at the global box office since 2002.

And rumor has it some of those previous Spider-Man actors, Tobey Maguire and Andrew Garfield, could join current star Tom Holland in the new movie. The "No Way Home" storyline revolves around Holland's Peter Parker trying to erase reality with the help of Doctor Strange after Parker's secret identity is revealed. That allows some former villains such as Alfred Molina's Doctor Octopus to show up — so it's possible some previous Spideys will, too.