The innovative design included wing flaps, variable-pitch propellers, and a tail-carrying full-length hull.

The prototype first flew on 29 March 1934, and, in the period of development and test flying that followed, quickly established ten world records for payload-to-height.

The new design would need increased lifting capacity to carry enough fuel and 300 lb (140 kg) of mail, but no passengers, for a 2,500 mi (4,000 km) nonstop flight against a 30 mph (50 km/h) headwind, at a higher cruising speed than the norm for similar flying boats at that time.

[1] Stripped of all accommodations, with extra fuel tanks in the fuselage, the S-42 was just able to fly proving flights across the Atlantic and Pacific oceans.

[9] British Marine Aircraft Ltd. was formed in February 1936 to produce S-42A flying boats under license in the United Kingdom but nothing came of this.

[13] According to Sikorsky, "Later on, another Pan American S-42 inaugurated the longest over ocean airline in the world from San Francisco to New Zealand.

[14] In March 1939 a Pan Am S-42 was scheduled to leave Miami at 0730, stop overnight in San Juan, Port of Spain, Belem and Recife, and arrive at Rio de Janeiro at 1530 on the fifth day.

In 1947, inventor Lemuel Stewart purchased the fuselage of S-42 NC-822M Brazilian Clipper from Pan Am for $750.00, converted it to a six-room houseboat, and kept it docked in a boat canal in Miami, Florida.

[29][30] On October 3, 1941, Pam Am Flight 203, an S-42A named Dominican Clipper, crashed on landing in the harbour at San Juan, Puerto Rico, killing two of 27 on board.

[33] On July 27, 1943, while docked at Manaus in Brazil a Pan Am S-42B named Bermuda Clipper (formerly Pan American Clipper III) developed an engine fire in response to which a flight engineer pulled the gas dump valve control instead of the fire extinguisher control.

After striking, bow first, the flying boat left the water in a slightly nose-high attitude, then returned, and by the third time, stalled.