When the New Museum of Contemporary Art opens its new headquarters on the Bowery this fall, it will become the first art museum to be built from the ground up south of 14th Street. The silver 60,000-square-foot, $35 million building will more than double the size of the museum’s former home in SoHo.

“We chose our location carefully,” the museum’s director, Lisa Phillips, said. “We wanted to be convenient to transportation and in touch with all the adjacent communities. It’s always been a social activist neighborhood as well as one friendly to artists. We’ll be a part of that. Our curators have already started checking out the artists in the neighborhood.”

If a major art institution opens on the Lower East Side, can a new flock of artists and galleries be far behind?

A few galleries, like Gracie Mansion (an icon in the 1980s), Kenkelebra House, and the Wilmer Jennings Gallery, never closed. Others, like the Rivington Arms and Participant, have opened within the past few years, drawing art lovers tired of Chelsea and SoHo’s tourist overload. The Abrons Art Center in the Henry Street Settlement has held exhibitions since 1975, as well as offering performances of theater, music, and dance.

But when the Woodward Gallery opens today at 133 Eldridge Street, it will be the first major SoHo gallery to make the move to the Lower East Side. Whether the directors, John and Kristine Woodward, will eventually be considered brilliant pioneers or foolish optimists, no one knows. For now, they are simply excited about the adventure, as they take up headquarters in a five-story building that once served as storage space for theater props, and as a synagogue before that.

“We’d been in SoHo 13 years, and long outgrown our place,” Mr. Woodward said recently. “But we were doing well and didn’t want to rock the boat — until our rent doubled last year. We then searched for another gallery in SoHo but just weren’t inspired. Huge rents for little space. We didn’t want to go to Chelsea; it has no soul.” So the couple began to look on the Lower East Side, where Mr. Woodward had lived during the ’80s and befriended Keith Haring, Jean-Michel Basquiat, Richard Hambleton and other artists. “They more than compensated for the negative aspects of the area, like the high crime and drugs,” he said. “The neighborhood resonates with me. I can see a fresh, vibrant art scene happening here again.”

The Lower East Side has long been a magnet for artists. In the ’50s and ’60s, Andy Warhol, Willem de Kooning, Franz Kline, Jasper Johns, Roy Lichtenstein, Jackson Pollock, Louise Nevelson, Mark Rothko, Kiki Smith, and many others made their homes there. In the late ’70s, another generation arrived, which, like its predecessor, created work that reveled in challenging the status quo.

By 1980, people were talking about — and buying, if they were smart — Kenny Scharf, Haring, Basquiat, and other mavericks, who were often as happy to make art on buildings as on canvases. But seven years later, a severe recession hastened the neighborhood’s rapid slide into hip oblivion.

Artists did not entirely disappear from the area, of course, but it lost its standing as a hotbed of experimentation even as it eventually became a trendy neighborhood with the right mix of derelict buildings, funky music venues, and chic wine and espresso bars. Lately, however, there have been signs of artistic revival, of which the Woodwards will soon be a part.

During the building’s six-month renovation, the couple made an all-out effort to strike up friendships in the community. On their block, they discovered a Buddhist temple, a synagogue, an excellent bakery and café, and, across the street, the hip Milk and Honey. Because the color red signifies good luck in the eyes of their Chinese neighbors, they painted the trim of the building fireengine red.

To get the most out of the new space, their architect, Elizabeth Hardwick of Giants in the Dirt, installed movable walls in the exhibition rooms on the first floor and in the basement, and designed a spacious area solely for private viewings and roomy climate-controlled storage space. It is quite a change from the gallery’s cramped 2,500-square-foot location on Broome Street. “Our artists are almost happier than we are,” Ms. Woodward said. “They see this place and all they can think of is how their paintings are going to look on these big walls.”

The Woodwards’ opening show, “When Art Worlds Collide: The ’60s,” celebrates the most traumatic period in late 20th-century art, which, to some extent, happened on the Lower East Side. During that period, the new Pop artists, who promoted a return to representational art, undermined the foundations of Abstract Expressionism. The show will include works on paper, paintings, and sculpture by artists of both worlds, including de Kooning, Robert Motherwell, Milton Resnick, James Rosenquist, David Hockney, and Georgia O’Keeffe.

From that ’60s collision eventually emerged Basquiat, Haring, and Mr. Hambleton, who still resides in the neighborhood. This spring, he joined the Woodwards’ stable of artists, which also includes Christina Vergano, Charles Yoder, Deborah Claxton, and Jo Ellen Van Ouwerkerk. Best known for his paintings of menacing black shadow figures that were once crudely splashed onto public walls in New York and other cities, Mr. Hambleton continues to paint his Shadow Man portraits on canvas, as well as gentle seascapes and landscapes. He will co-curate a major exhibition at the gallery next year, focusing on the new street art scene.

“We’re hoping Richard will come to the opening,” Mr. Woodward said. “For some of us, the old Lower East Side spirit never dies.”