HSRL is the oldest experiment station of its kind in the country. Research in shellfisheries at Rutgers began in 1888 when Julius Nelson was hired as the biologist for the newly formed New Jersey Agricultural Experiment Station. He felt strongly that the practices of the oyster industry were much like those of a farmer (i.e., oystermen "planted" "seed", which they "cultivated" on "surveyed" grounds and then "harvested", after which they occasionally let their "ground" lie "fallow") and persuaded the Experiment Station to establish a Department of Oyster Culture. In 1901, the New Jersey Legislature recognized the value of Nelson's work and granted him $200 to build a small laboratory near Tuckerton. The "Oyster Investigation Laboratory", as it was then known, grew rapidly.

A second laboratory was built at Barnegat in 1905 and, in 1909, the houseboat Cynthia, which could be towed to sites of biological interest along the New Jersey coast, was constructed. Julius Nelson died in 1916 and was succeeded by his son, Thurlow. During Thurlow Nelson's tenure as director, laboratories were built in Bivalve (the home port of the Delaware Bay oyster fleet) in 1923 and on the bay shore of the Cape May Peninsula (Cape Shore) in 1928. Laboratories remain at these two sites today.

In 1950, Harold Haskin, who had studied with Thurlow Nelson, assumed the directorship of the Oyster Laboratory. Under his leadership, shellfish studies branched out to include hard clams and surf clams. When epizootic mortalities caused by MSX disease began in 1957, a major, continuing program was created to understand and devise control methods, including a breeding program to develop strains resistant to the disease. In the late 1970s, at the instigation of the oyster industry and with the strong support of local communities, federal funding was obtained to build a large new laboratory at Bivalve. The building was completed in 1982 and has had two additions since then. A new hatchery was built at the Cape Shore laboratory in 1994.

Harold Haskin retired in 1984. In recognition of his contributions to the University and marine resources throughout the state, the Rutgers Board named the station after him in 1991 (the first University facility named after a living person). Haskin was replaced as Director by Richard Lutz. A major change during Lutz's tenure was the incorporation of the HSRL and the Department of Oyster Culture into the Institute and Department (respectively) of Marine and Coastal Sciences. During this time, research at the HSRL continued to focus on oysters, with increased emphasis on genetics, pathobiology, and new directions in cell biology and aquaculture. Long-term studies continued on oyster populations in upper Delaware Bay, including advising resource managers and oyster growers. In 1995, Lutz was replaced as Director by Eric Powell.