The Order took an active role during conflicts, beginning with the Franco-Prussian War and the Turco-Serbian Wars of the 1870s.

A conference held by the British government in 1898 led to the formation of the Central British Red Cross Committee, to co-ordinate medical support for the British forces during wartime.

In 1899, the Anglo-Boer War (1899-1902) broke out in South Africa, and St John volunteers provided valuable support to army medical services. By the time the First World War began in 1914,

St John and the Red Cross were well prepared, and the Military Home Hospitals Reserve and Royal Naval Auxiliary Sick Berth Reserve were quickly mobilised. In recognition of their courage, the title of the Order was changed to The Most Venerable Order in 1936.

During the Second World War of 1939 to 1945 many thousands of St John volunteers worked with the army and navy overseas, and at home. When German bombing raids hit civilian targets in the UK during the Blitz, the Order provided both medical treatment and first aid training.

Towards the end of the war, St John volunteers were among the first to provide relief to those imprisoned in Nazi concentration camps.