It is the direct descendant of the 6.5×53mmR rimmed cartridge from the 1891 Mannlicher rifle, designed to function smoothly through the Schönauer's rotary magazine.

[2] Walter Dalrymple Maitland "Karamojo" Bell, who shot 1,011 elephants[3] in the period 1895–1930, had a very high regard for the 6.5mm Mannlicher–Schoenauer, using it for approximately 300 of these kills.

[7] In part, the 6.5×54mm's reputation stems from its use of a 160-grain (10 g) bullet, giving the projectile very high sectional density and therefore penetrating ability.

From 1906 until the German invasion and capitulation of Greece in April 1941, it was the standard military cartridge of the Greek Army.

During the German occupation, Carcano rifles captured during World War II were also converted to 6.5×54mm Mannlicher–Schönauer and used by Greek forces.