The shoreline and bluffs of the Reserve were first visited and settled by Native Americans, as evidenced by the four remaining cultural resource sites, one of which has been dated at about 5,800 years. In the mid-18th Century, Portola and his expedition were fed by Native Americans near Pillar Point. The landscaping at the Smith-Dolger home site, dating back to the early 1900s, remains as the only documented historical site within the Reserve.

The shoreline and reefs within the Fitzgerald Marine Reserve have been of interest for many years to marine biologists, preservationists and collectors. At least since 1908, when the Ocean Shore Railroad was extended into the area, Moss Beach had been used extensively as a resort and by people gathering food from the reef. It has long been known to biologists and teachers as one of the best places for collecting inter-tidal invertebrates. As early as 1911, Dr. S. F. Light brought his zoology classes from the University of California. Due to its popularity, the resource was being depleted, and in the 1960s, San Mateo County proposed that the State of California acquire the area as a state reserve.

The Ecological Reserve is a State of California designation authorized by the Marine Resources Protection Act of 1990 (California Fish and Game Code, Article 4, Section 1580-1584). Ecological reserves are intended to protect natural areas and use can be restricted to scientific research relating to the management and enhancement of marine resources. Except as authorized in conjunction with scientific research approved by the California Department of Fish and Game and the San Mateo County Department of Parks, no disturbance or taking of marine life, archaeological resources or geological formations is allowed, and no fishing or collecting is permitted. Public entry into an ecological reserve may be restricted to protect resources.

Pillar Point Marsh was dammed by farmers in the earlier part of the century, in order to prevent salt water from moving into upland farming areas, and to provide a means by which farm equipment could cross the marsh for access to the slopes above the marsh for farming. In the late 1920s, the US Air Force built West Point Avenue as an access road across the dam to reach the military installation on the bluff above Pillar Point. The Army Corps of Engineers constructed the breakwater around Pillar Point Harbor in 1962, to create a safe refuge for small vessels.