In 1950, Reddy was nominated to the Provisional Parliament and was appointed Whip of Congress Parliamentary Party.

In 1962 he was again elected, now from Tandur Constituency, and was Minister for Planning and Panchayat Raj and later for Finance, Commercial Taxes and Industries.

He resigned the State Ministry on his appointment as Minister for Steel, Mines and Metals in the Union Cabinet (1967–68).

Reddy took an active part in several public movements and played a notable role in the split of the Congress political party.

This was later incorporated as 'New Deal for Telangana' in the Congress Manifesto when the elections to the Andhra Pradesh Assembly took place in 1972.

In 1974, Reddy accepted the office of Governor of Uttar Pradesh, the most populous State of the country on a reported personal plea of Indira Gandhi made that she required Reddy's assistance to help her as the Governor of Uttar Pradesh, her home State.

[4] As Chancellor for the state Universities, he set a practice of conferring Honorary Degrees on great scholars and renowned scientists from others parts of the country, particularly, from the South.

He sought advice from leaders of repute and public men like Nirmal Chandra Chaturvedi, CB Gupta and Ali Zaheer to cleanse the state administration.

He has also been Governor of Uttar Pradesh (during president rule in the mid-1970s), Rajasthan, Punjab, Tamil Nadu and Pondicheri.

His younger son, Marri Shashidhar Reddy, was Vice Chairman of National Disaster Management Authority (NDMA) with a Union Cabinet status; he was also a four-time MLA from Sanathnagar.

He was taken to a private hospital in the city after he complained of a chest pain at around midnight before he slipped into coma.