Acquiring about 12,900 acres (52.2 km2) in the Town of Newcomb, just south of the Adirondack High Peaks, Pruyn employed the distinguished architect Robert H. Robertson (1849–1914) to design a summer residential complex.

Robert C. Pruyn's heirs in 1953 sold the Santanoni Preserve to the Melvin family, leaders in the business and professional community of Syracuse, New York.

For two decades Camp Santanoni buildings were inadequately maintained by the state, since the intent, as required by the Article Fourteen of the New York State Constitution (providing for retention of Adirondack wilderness) was to remove improvements in order to return the Santanoni Preserve to a "forever wild' condition.

With imported and domestic breeds of cattle, sheep, goats, pigs and poultry, Santanoni had probably the largest farm operation ever associated with a family estate in the Adirondacks.

It supplied the camp with its meat and produce, while surplus dairy products were sold in Newcomb and sent to Albany for the Pruyns and their friends.

The Main Camp was situated 4.7 miles (7.6 km) from the Gate Lodge complex, farther into the estate on the shore of Newcomb Lake, with an excellent view toward the Adirondack High Peaks.

With its log grill work on the eaves, birch-bark wall covering and hand-hewn beams in the two-story high ceiling of the main living area, half-log decorative patterns on many walls and doors, impressive fieldstone fireplaces, and other structural and decorative features, Santanoni is an outstanding example of rustic Adirondack Architecture and the craft of log construction.

Theodore Roosevelt and James Fenimore Cooper, Jr. were among the many distinguished visitors who regularly visited the Pruyns at their Adirondack camp.

Funds from the Getty Foundation Grant Program assisted development of the Conservation Plan, which has guided all recent work.