Sikorsky designed the S-40 in response to a request from Juan Trippe, president of Pan American Airways, for a larger passenger-carrying airplane.

[1] The aircraft featured a pantry with an electric refrigerator and stove as well as a smoking lounge with book-ended mahogany wood paneling.

[2] Despite a significant size increase over the preceding S-38, the S-40 design was a conservative iteration of the smaller aircraft;[3]: 62  the numerous flying wires and strut braces that were used in the exterior support framework caused significant drag and prompted Charles Lindbergh, retained as a consultant for Pan American, to tell Sikorsky "it would be like flying a forest through the air.

"[4][5]: 57  Only three were built as Sikorsky began designing the more advanced and streamlined S-42 shortly after the S-40 entered service,[3]: 62–63  based partly on input from Lindbergh.

[11] Passenger carrying service was initiated on November 19, 1931, with a S-40 piloted by Charles Lindbergh and Basil Rowe, flying from Miami, Florida to the Panama Canal Zone with stops at Cienfuegos, Cuba; Kingston, Jamaica, and Barranquilla, Colombia.

[13] In July 1943, an RS-4 (752V) was coming in for beaching when it struck an unforeseen submerged rock, which damaged the wheel strut, which in turn caused a list that led to a pontoon striking a rail at the edge of ramp.