Retractable landing gear and a streamlined fuselage added to the aerodynamic efficiency of the aircraft.

A single example was constructed for evaluation by both Boeing and the US Army (under the designation Y1C-18) but no mass production ensued, and the aircraft eventually joined Boeing's fleet on the San Francisco-Chicago air mail route from July 1931.

A second version was developed as the Model 221, with a fuselage stretched by 8 inches (20 cm) that sacrificed some of its cargo capacity to carry six passengers in an enclosed cabin; the single pilot, however, sat in an open cockpit.

The advanced design of the Monomail was hampered by the lack of suitable engine and propeller technology.

By the time variable-pitch propellers and more powerful engines were available, the design had been surpassed by multi-engined aircraft, including Boeing's own 247.