The first operator of the S.73 was the Belgian airline SABENA, which purchased five Gnome-Rhône 9Kfr Mistral Major-powered S.73s from Savoia-Marchetti in 1935, introducing them on European routes in the summer of 1935.

Seven more S.73s, powered by Gnome-Rhône 14K Mistral Major engines, were built for SABENA under license by SABCA in 1936–1937, which allowed the S.73 to replace the Fokker F.VII on the service from Belgium to the Congo.

[3][4] The second operator of the S.73 was the Italian airline Ala Littoria, which received at least 21 examples, powered by a variety of engines, including the Piaggio Stella X, the Wright R-1820 and the Alfa Romeo 126 RC.10.

[3] In December 1935, an S.73 was used for a journey from Italy to Asmara, delivering over 200,000 letters, with 6,600 km (4,100 mi) traveled in four days, followed by the return trip to Rome on 6 January 1936.

[5] At the outbreak of World War II the S.73 was already obsolete, but some of the aircraft were pressed into service with the Regia Aeronautica for operations in Abyssinia and Spain.

[6] Owing to the poor military situation, with British Commonwealth forces on the brink of capturing Addis Ababa, the Duke of Aosta, the Viceroy of Italian East Africa, ordered the remaining three S.73s to be evacuated.

After several days of preparation, they took off from Addis Ababa on 3 April 1941 with 36 men on board, planning to fly to Kufra in Libya, 2,500 km (1,600 mi) away, requiring additional fuel tanks in the fuselage.

Two aircraft, after 10 hours of flying and the men inside almost killed by fumes of the fuel auxiliary tanks, landed at Benghazi, after 4,500 km (2,800 mi) and over a month of travel.

After two were destroyed by the Luftwaffe at Merville on 23 May, SABENA ordered its surviving aircraft, including the five S.73s, to move to France in preparation for transfer to the Belgian Congo.