Greene Street Friends School was founded in 1855 by Quakers in Germantown. It has operated continuously at its current location. In the first half of the 20th century, most of Greene Street's enrollment was female. Boys typically left the school after first grade to attend other boys schools that were in the neighborhood. Around 1960, Greene Street instituted coeducation and increased the School's racial diversity to nearly 50%, a figure that the School has maintained ever since.
In 1948, Greene Street joined with about 20 other schools to found the forerunner of PAIS, the Pennsylvania Association of Independent Schools. As a charter member, Greene Street continues to participate actively in the accreditation of independent schools in the Commonwealth of Pennsylvania.
In the 1990's the School began a long term effort to expand its enrollment, educating two classes per grade, a process that is now completed. To accommodate increased enrollment the School has acquired four properties, doubling the size of its indoor and outdoor spaces.