Rama Rao was born on 20 May 1983 in Hyderabad to Telugu film actor and politician Nandamuri Harikrishna and Shalini Bhaskar Rao. His mother is from Kundapur, Karnataka. He is the grandson of Telugu actor and former Chief Minister of Andhra Pradesh N. T. Rama Rao. He did his schooling at Vidyaranya High School, Hyderabad, and completed his Intermediate education at St. Mary’s College, Hyderabad. He is a trained Kuchipudi dancer.

Rama Rao collaborated with director Rajamouli for the third time for a socio-fantasy film Yamadonga. For this film, he had to sport a new look by shedding more than 20 kg, as he used to be 94 kg. Rao played Raja, a thief who later criticizes and insults Yama and then suddenly goes into hell due to some bad acts. The film received extremely positive reviews, and later brought him back to the top league in Telugu cinema, and this film made him receive a Filmfare Award for Best Actor in Telugu. Actor Sobhan Babu praised Rama Rao’s performance in the film. Rama Rao later signed up for the action film Kantri which was directed by debutant Meher Ramesh a protege of Puri Jagannadh. In 2009, Rama Rao took a year hiatus to campaign for Telugu Desam Party (TDP) in the 2009 general elections.

Rama Rao was one of the campaigners for the Telugu Desam Party, for the 2009 Indian general election from April to May 2009 in Andhra Pradesh. On 26 March 2009, after electioneering, en route to Hyderabad, the SUV in which he was a passenger, was struck head-on with another vehicle, at Suryapet. He and his companions were thrown out off the SUV and suffered injuries. He was treated at Krishna Institute of Medical Sciences, in Secunderabad, where he recuperated well.

In 2009, Rama announced that he intended to donate 20 lakhs to Chief Minister’s Relief Fund to take up relief operations for flood victims. During Baadshah audio function in 2013, a fan died due to a heavy stampede, NTR donated 5 lakhs to his family. Rama Rao also promised to take care of his family, due to the fan’s sudden demise.

Rama Rao married Lakshmi Pranathi, on 5 May 2011 at Hyderabad at Hitex Exhibition Center, Madhapur. They have two sons.

In 2014, Rama Rao announced that he intended to donate 20 lakhs to CM’s Relief Fund to take up relief operations for victims of Cyclone Hudhud in Andhra Pradesh.

In 2015, he starred in Temper directed by director Puri Jagannadh. The film gave a much-needed success for Rama Rao, after a series of debacles and his performance as a corrupted cop Daya who turns a good doer was appreciated by audience and critics alike.

Following the success of Temper, Rama Rao worked in Nannaku Prematho (2016) directed by Sukumar under the production of Sri Venkateswara Cine Chitra and Reliance Entertainment. He has second Filmfare Award for Best Actor – Telugu for his performance. NTR sported a new look with gelled up hair and long beard for the film. received positive reviews from critics and audience. The movie eventually turned out to be the highest grosser in Rama Rao’s career surpassing Baadshah with a worldwide gross of ₹82.7 crore (US$12 million). Later in the same year, Rama Rao starred in the September release Janatha Garage, directed by Koratala Siva, where he was cast alongside the Malayalam actor Mohanlal. The film registered the highest opening for a Tollywood film in 2016, and was the second highest Tollywood opening of all time, behind Baahubali: The Beginning. and became the highest grossing Telugu film of the year.

In 2017, Rama Rao essayed a triple role in Jai Lava Kusa under the direction of K. S. Ravindra on N.T.R. Arts banner with his half-brother Nandamuri Kalyan Ram as the producer. Jai Lava Kusa collected almost ₹130.90 worldwide and was successful at the box office with critics praising his triple role performance.

In 2018, he starred in Trivikram Srinivas-directed action drama Aravinda Sametha which went become one of the highest-grossing Tollywood films of the year. S. S. Rajamouli’s magnum opus RRR, where Rama Rao playing 20th century freedom fighter Komaram Bheem, is under production.