Zakir Hussain was born in the state of Hyderabad in central India. He was a Pashtun Muslim from Punjab who belonged to the Khesgi and Afridi tribes. They first settled in Malihabad in the United Provinces before moving to the Deccan in the 19th century. When Zakir Hussain was a young boy, his family moved from Hyderabad to Qaimganj. This is where he grew up, and likewise, he remained more closely connected with Kayamganj in Farrukhabad district.

Zakir Hussain was the second of seven sons. Many, indeed, most of his family members opted to embrace Pakistan over the partition of India. His brother Mahmud Hussain had joined the Pakistan movement many years before Partition and was a major light of Jinnah's Muslim League to the extent that he was made a member of the Constituent Assembly of Pakistan. Starting in 1951, he served as Education Minister of Pakistan and Minister of Kashmir for a significant time. Zakir Hussain's nephew, Anwar Hussain, served as a director of Pakistan Television Corporation. A cousin, Rahimuddin Khan, served as chairman of the Pakistan Army, Joint Staff Committee and Governor of Balochistan and Sindh.

The relatives of Zakir Hussain, who chose to remain in India, performed as well for themselves under the patronage of the Congress Party as both before and after Zakir Hussain, who held the topmost office of the land. His younger brother Yusuf Hussain became the Pro-Vice-Chancellor of Aligarh Muslim University, while his nephew, Masood Zakir Hussain, was the Vice-Chancellor of Jamia Millia Islamia. Zakir Hussain's own son-in-law Khurshid Alam Khan served as the Governor of Karnataka for many years and his grandson, Salman Khurshid, a Congress Party politician, was the External Affairs Minister of India under Manmohan Singh. Zakir Hussain's father, Fida Hussain Khan, died at the age of ten, his mother died at the age of fourteen. Zakir Hussain completed his primary elementary education in Hyderabad, completed high school from Islamia High School, Etawah and then graduated in Economics from Christian Degree College, Lucknow University. After graduation, he moved to Muhammad's Anglo-Oriental College, then joined the University of Allahabad, where he was a prominent student leader. He received his doctorate in economics from the University of Berlin in 1926. In 1915, at the age of 18, he married Shah Jahan Begum and had two daughters, Saeeda Khan and Safia Rehman.

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