The Airone saw more than 20 years of service. The Z.506B was first used as a reconnaissance aircraft and torpedo bomber in the Spanish Civil War. When Italy entered the war, on 10 June 1940, 97 aircraft were operational with two Stormi da Bombardamento Marittimo (sea bombing units) and some Squadriglia da Ricognizione Marittima. 31°Stormo B.M. "autonomo" with 22 planes was based at Cagliari-Elmas airport, in Sardinia; 35° Stormo B.M., with 25 Z.506 in Brindisi, Puglia. It was used extensively in 1940-41 in France and Greece. On the outbreak of World War II, four Squadriglie for air-sea rescue missions were formed in Orbetello. These were the 612a in Stagnoni, with aircraft marked DAMB, GORO, BUIE, CANT (the prototype) and POLA, and the 614a in Benghazi, with DUCO, ALA, DODO and DAIM. The two other sections with two aircraft each were based in Torre del Lago and in the Aegean Sea at Leros. The latter was later transferred to Rhodes.
The Z.506 had its baptism of fire on 17 June 1940, the day after some French bombers had attacked Elmas base, killing 21 airmen and destroying some Cant. Z.501s. On the evening of 17 June, four 506Bs from 31° Stormo attacked targets in Northern French Africa, each dropping two 250 kg and three 100 kg bombs. The type also took part in the Battle of Calabria. In the war against Greece it was used against coastal targets and the Corinth canal. It played an important part in the conquest of many Greek islands, including Corfu, Cephalonia and Zante. Due to its vulnerability against fighters, it was restricted to use by 'recce' units (Squadriglie da Ricognizione). Later in the war, it was used in maritime patrol and air-sea rescue missions. The 506 was often forced to land in Spain, due to engine failure, combat damage or a lack of fuel. A special air-sea rescue version, the Z.506S Soccorso, was produced; it was used in small numbers by the Luftwaffe.