The son of the leading attorney of his native city, Zafrulla Khan studied at Government College in Lahore and received his LL.B. from King's College, London University, in 1914. He practiced law in Sialkot and Lahore, became a member of the Punjab Legislative Council in 1926, and was a delegate in 1930, 1931, and 1932 to the Round Table Conferences on Indian reforms in London. In 1931–32 he was president of the All-India Muslim League, and he sat on the British viceroy's executive council as its Muslim member from 1935 to 1941. He led the Indian delegation to the League of Nations in 1939, and from 1941 to 1947 he served as a judge of the Federal Court of India.

Prior to the partition of India in 1947, Zafrulla Khan presented the Muslim League's view of the future boundaries of Pakistan to Sir Cyril Radcliffe, the man delegated to decide the boundaries between India and Pakistan. Upon the independence of Pakistan, Zafrulla Khan became the new nation's minister of foreign affairs and served concurrently as leader of Pakistan's delegation to the UN (1947–54). From 1954 to 1961 he served as a member of the International Court of Justice at The Hague. He again represented Pakistan at the UN in 1961–64 and served as president of the UN General Assembly in 1962–63. Returning to the International Court of Justice in 1964, he served as the court's president from 1970 to 1973. He was knighted in 1935 and was the author of Islam: Its Meaning for Modern Man (1962) and a translation of the Qurʾān (1970).