NTR Mahanayakudu is the sequel to the first film that depicted the life of the veteran actor, Nandamuri Taraka Rama Rao (Balakrishna) on the big screen. After establishing his political party, Telugu Desam, Rama Rao with the help of his son, Hari Krishna (Nandamuri Kalyan Ram), sets out to gain support and trust of the people. He restores the glory and importance of Telugu people and earns their respect. He travels and understands the problems of people in his state. After a series of hurdles, he gets appointed as the Chief Minister of combined Andhra Pradesh. He introduces several projects that benefit the common man. These include - Kg rice for Rs. 2, equal rights for a girl child in father's property, establishing Mandal system, Telugu Ganga Project among the others. Everything doesn't happen smoothly and several hurdles from within his party and the center try to stop his progress. However, the man faces them all. In between all this, his wife, Basavaramatarakam (Vidya Balan), gets diagnosed with Cancer and falls ill. Despite this, he works for his people and balances personal life with professional using the help of his son-in-law, Chandra Babu Naidu (Rana Daggubati). How he battles corruption, destroys crimes and makes his place in the hearts of people forms the story of the biopic.