A certain street corner in Weehawken, N.J., looks a lot like any other. The difference is that this intersection just across the Hudson River from New York has been immortalized in a painting worth millions.

The work, "East Wind Over Weehawken," by American realist Edward Hopper, is about to go on the auction block for the first time. Such an offering is a rare event, according to Elizabeth Sterling, Christie's head of American Art.

"Hopper was not that prolific in oil painting, and the majority of his works are in [museums]," she said.

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Considered one of the great artists of the 20th century, Hopper is known for scenes from the 1930s. "East Wind Over Weehawken," done in 1934, illustrates a desolate street during the Great Depression, with a "for sale" sign and overgrown lawns the focal points.

Hopper captured what many Americans faced in one of our most difficult times, experts say.

"Hopper was trying to get a sense of the economic turmoil," Sterling said. "Rather than depicting homeless people on the street like most of his peers did, he took this quiet street in Weehawken to show the ramifications of [the Depression] on a domestic level."

"East Wind Over Weehawken" is expected to fetch between $22 million and $28 million when it is offered on Dec. 5. And who are the likely bidders?

"We've been seeing international interest, but I think it's going to an American collector—just based on what we've been seeing for past Hoppers," Sterling said. "It's been international participation, but ultimately the highest bidder for the past few years has been American."

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Whoever places the winning bid could set a new record for Hopper's work at auction. The previous record, in 2006, was $27 million for his "Hotel Window."

—By CNBC's Erica Emmich. Follow her on Twitter and Instagram: @MegaMoneyGal

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