Envisioned as corporate or private "flying yachts" for Manhattan millionaires, initial production models normally carried two to three passengers and had a bar and small toilet installed. As well as being marketed to small air carriers, the G-21 was also promoted as a military transport. In 1938, the U.S. Army Air Force purchased the type as the OA-9 (later, in the war years, examples impressed from civilian ownership were designated the OA-13A). The most numerous of the military versions were the United States Navy variants, designated the JRF.

The amphibian was soon adopted by the Coast Guard and, during World War II, it also served with the RCAF in the transport, reconnaissance, rescue and training roles. The G.21 was used for air-sea rescue duties by the Royal Air Force (RAF). The RAF, in a common naming convention with all of its aircraft, designated the type as "Goose."

On returning to civilian service, after the war, the Goose found continued commercial use in locations from the wilderness of Alaska to the sunny climes of Catalina.

A total of 345 were built, with about 30 still airworthy today (although more like 60 are still on various civil registries, many of them are known to have crashed or been otherwise destroyed), most being in private ownership, some of them operating in modified forms.