The church building was designed by architect Stanford White, with stained glass windows by John La Farge.

In 1921, under the leadership of its pastor, A. Ray Petty, the church offered first its basement and then rented its parish house on Thompson Street to Dr. Eleanor A. Campbell, a pioneering female physician who ran the Judson Health Center, a free medical and dental clinic.

Although the congregation dwindled, the church remained active in various social causes, including allowing homeless men to sleep on the pews at times.

At the same time, a new pastor, Robert Spike, began theological explorations with veterans and the artists then working in the village, which brought a new group of congregants and led to a change in the church's worship style to a more modern sensibility.

In 1956, Howard Moody became the senior minister, continuing the church's outspoken advocacy on issues of civil rights and free expression, as well as breaking with the confessedly evangelical understandings of the past by speaking out for issues once universally considered to be immoral by Christians (such as abortion and the decriminalization of prostitution), a policy that continues under the present leadership of the congregation.

The congregation expanded during this period, allowing the church to take back control of its property from the citywide Baptist organization that had been acting as trustee until 1973.

In the first decade of the 21st century, the church's clergy operated a relief fund for the families of restaurant workers who were killed during the September 11, 2001, attacks of New York City's World Trade Center.

Henderson appeared in courts on behalf of those facing legal action and began summer youth programs in upstate New York and Vermont.

Henderson once invited Martha Graham to use the sanctuary for dress rehearsals, which eventually led to formation of the Judson Dance Theatre.

The Judson Dance Theater, which began in 1962, provided a venue for dancers and choreographers including Trisha Brown, Lucinda Childs, Steve Paxton, Deborah Hay, David Gordon and Yvonne Rainer to create and show their work.

For the past several decades, Movement Research has presented concerts of experimental dance at the church on Monday evenings during the academic year.

The exhibit and the accompanying symposium, featuring speeches by Abbie Hoffman and Kate Millett, attracted widespread attention from the public, the press and the police.

Experimental plays and musicals by later-famous authors and directors, including Sam Shepherd, Lanford Wilson and Tom O'Horgan, were presented in the church's main Meeting Room.

Especially notable were several shows using texts by Gertrude Stein, music by Carmines, with direction by the Judson Poets Theatre director Lawrence Kornfeld.

The campanile tower, located at 51–54 Washington Square South to the west of the church itself, was built in 1895–96, after the sanctuary had been completed, and was designed by the firm of McKim, Mead & White.

At eleven stories tall, the new building now towers over the church and Washington Square Park beyond, causing considerable controversy in the community at the time of its construction.