After graduating from Oxford in 1900, Humphrys joined the Worcestershire Regiment and served in the Second Boer War. Following the war he was in February 1902 seconded to the Indian Staff Corps, and in October the same year he left his regiment and was transferred to the Indian Army. He was seconded to the Political Service and spent most of this part of his career in the North-West Frontier Province, although in 1918, towards the end of World War I he returned to Europe and served with a temporary commission in the newly formed Royal Air Force. In 1919 he returned to India, first as a political agent and then, in 1921, as deputy Foreign Secretary in the Government of India. Following the Anglo-Afghan "Treaty of Kabul" of 22 November 1921, in early 1922 Humphrys was appointed the first British Minister to the Amir of Afghanistan, Amānullāh Khān. In November 1928 a rebellion began in Jalalabad and tribal forces marched on Kabul, and in early 1929 Humphrys supervised the evacuation by air of several hundred Europeans in what became known as the Kabul Airlift. In the House of Commons on 4 February the Foreign Secretary, Austen Chamberlain, commended both Humphrys and his wife for their 'courage and fortitude'. In the King's Birthday Honours of that year Humphrys was given the additional knighthood of KCMG and Lady Humphrys was made DBE. Later in 1929 Humphrys was appointed to be High Commissioner in the Kingdom of Iraq, then under British administration. Following the Anglo-Iraqi Treaty, which Humphrys signed for the United Kingdom, on 3 October 1932 Iraq became an independent kingdom and Humphrys became the first British Ambassador to Iraq. In 1935 Humphrys retired from the diplomatic service and was appointed chairman of a Sugar Tribunal which resulted in the creation of the British Sugar Corporation, of which he was chairman from its formation in 1936 until 1949. He was also director of several other companies and was chairman of Iraq Petroleum Company 1941–50.
Francis Humphrys was knighted KBE in the King's Birthday Honours of 1924, awarded the additional honours of GCVO in 1928 and KCMG in 1929, and promoted GCMG in the New Year Honours of 1932. Amānullāh Khān made him a member of the Nishan-i-Sardari, with the title of Sardar-i-ala, in 1928; the King of Iraq awarded him the Grand Cordon of the Wisam al-Rafidain in 1933.