Under the direction of the Commissione delle Armi Portatili (commission for portable weapons), instituted in 1888, to develop a smokeless-powder rifle for the Italian Army, the Reale Laboratorio Pirotecnico di Bologna (royal pyrotechnical laboratory of Bologna) developed and tried several different cartridge designs, with bullet diameters from 6 to 8mm.

After the adoption of the cartridge, the arsenal's technicians worried about the characteristics of the original ballistite load, since that propellant was considered too erosive (flame temperature of 3,000-3,500 °C) and not stable under severe climatic conditions.

The 6.5×52mm Carcano was the first to be officially adopted of a class of similar smallbore military rifle cartridges which included the 6.5×50mm Arisaka (Japan), 6.5×53mmR Mannlicher (Romania/Netherlands), 6.5×54mm Mannlicher–Schönauer (Greece), 6.5×55mm Swedish Mauser (also Norwegian Krag–Jørgensen), and the Portuguese 6.5×58mm Vergueiro.

A comparison with larger-bore smokeless powder cartridges of the 7 and 8 mm calibre class (such as the French 8×50mmR Lebel, the German 7.92×57mm, the Austrian 8×50mmR Mannlicher, the .303 British, the Russian 7.62×54mmR, the Belgian and 7.65×53mm Argentine, the American .30-40 Krag, and the much later .30-03 and .30-06 Springfield) may make the 6.5mm rounds appear underpowered on paper, and lacking in stopping power.

However, the small bore cartridges have a long list of advantages, such as flatness of trajectory, outstanding penetration at distance, less weight, less recoil, smaller dimensions, and less material required in production.

[2] However, the standard Italian service round used an unstable round-nosed bullet with a propensity to tumble, whether hitting soft tissue/ballistic gel or harder material such as bone.

Dubbed the humanitarian by members of the Warren Commission, due to perceived deficits in quality and performance, it has never enjoyed more than a cult following by collectors and historians.

[6] The cartridge was identified by the Warren Commission as the round used in a World War II–surplus Italian 1891 Carcano (Fucile di Fanteria Mod.