Dr. Thomas Wynne, Welsh physician to William Penn and Speaker of the first two provincial assemblies of Pennsylvania, gave the neighborhood its name when he built his home, Wynnestay, in 1690.  Stay is Welsh for field. The house still stands at the corner of 52nd and Woodbine.

Around 1904, the Wynnefield Improvement Company built several homes in the area in the style of Wynnestay.  In the 1920s, the numerous row homes throughout the area were built.  In the 1950s, the two shopping areas in the neighborhood gained prominence; one at City Line and 47th Street , and the other at 54th Street near City Line.

With the opening of the Wynnefield Branch in June 1964, the current configuration of the neighborhood was completed.  The building was the end result of a long campaign by the Wynnefield Residents Association, and included the establishment of the Wynnefield (now John C. Anderson) Cultural Center under the direction of the City of Philadelphia Department of Recreation.

In September 2000, the Wynnefield Branch re-opened after extensive technological upgrades and the addition of several public computers.