In 1895, the trustees and the Business Committee of the Board of Publication and Sabbath School Work (PCUSA) appointed a Subcommittee on New Building. Its purpose was to manage and oversee the construction of a new building to house various PCUSA offices, including the Board of Publication and Sabbath School Work, the Presbyterian Historical Society, and General Assembly offices. The lot purchased for the new building was in Philadelphia, extending along Juniper Street from Walnut Street to Sansom Street. The committee elected to name the building in honor of the Rev. John Witherspoon, first president of the College of New Jersey (Princeton University), member of the Second Continental Congress, and the only clergyman to sign the Declaration of Independence.

In June of 1895, Joseph M. Huston was selected as the architect. The committee intended that the Witherspoon Building should be "an ornament to the city, a fit exponent of the strength and capacity of the Presbyterian Church, and a centre of beneficent power and religious influence for the elevation and enlightenment of the whole country." The decoration of the building reflects this attempt to tell the story of American Presbyterianism in steel, granite and terra cotta. Samuel Murray (in collaboration with Thomas Eakins) sculpted ten larger-than-life-size statues of Biblical prophets which stood at the building's corners and along the walls high above the street at the eighth floor level, and Alexander Stirling Calder carved six statues of fathers of American Presbyterianism which stood above the main doors. The building was further decorated with carved medallions, some of figures from the Bible and from American history, and others bearing seals and insignia of various Presbyterian organizations.

The 11-story Witherspoon Building remained the headquarters of the Board of Christian Education, the Historical Society, and other Presbyterian offices until the 1960s. The Historical Society moved to a building of its own in 1967. In 1973, as a part of the reorganization of General Assembly agencies, the General Secretary of the Board of Christian Education sold the Witherspoon Building. Though the statues of prophets and Presbyterians have been removed, the Witherspoon Building remains standing and is still in use as an office building.