Hussain was born in Hyderabad India. His Pashtun father had migrated to Hyderabad from Uttar Pradesh. He was educated at Islamia High School in Secunderabad, and at the Anglo-Muhammadan Oriental College (now Aligarh Muslim University).
Hussain, then only 23, was among the small group of students and teachers who founded a National Muslim University near Delhi and named it Jamia Millia Islamia. Hussain's thirst for knowledge took him to Germany in the 1920s. During three years of stay there, he acquired a love for European art, literature and music. He was awarded a doctorate in economics from the University of Berlin. After serving as the Governor of Bihar from 1957 to 1962, and as the Vice President of India from 1962 to 1967, Hussain was elected President of India on May 13, 1967. In his inaugural speech he said that the whole of India was his home and all its people were his family. Hussain was also the uncle of General Rahimuddin Khan. He was awarded the highest Indian national honour, the Bharat Ratna in 1963.