Akkineni Nagarjuna was born on 29 August 1959 at Chennai, Tamil Nadu to veteran actor Nageswara Rao Akkineni and his wife Annapoorna Akkineni. The family later moved to Hyderabad, where he attended the Hyderabad Public School and Little Flower Junior College. He completed one year of his Bachelor of Engineering from the College of Engineering, Guindy, and earned his B.S. in Automobile Engineering from Eastern Michigan University in Ypsilanti, Michigan.

Nagarjuna began acting as a child Artist in the 1967 Telugu film Sudigundalu directed by veteran Adurthi Subbarao. It starred his father Akkineni Nageswara Rao in the lead role. Years later he made his debut as a lead actor through the 1986 Telugu film Vikram, directed by V. Madhusudhana Rao. It is the remake of the 1983 Hindi film Hero. The film was a success, giving Nagarjuna a good start.

Nagarjuna has been married twice. In 1984, he married Lakshmi Daggubati, a member of the Daggubati family which is prominent in the Telugu film industry. She is the daughter of D. Ramanaidu, a prominent film-maker, and sister of the actors Venkatesh and Suresh Babu. Lakshmi bore Nagarjuna a son, the actor Naga Chaitanya (born in 1986). However, the couple were divorced in 1990, an event which caused much upheaval in the Telugu film industry because of the falling out of its two most powerful families. Nagarjuna then married the Actress Amala Akkineni. By his second wife, Nagarjuna is the father of another son, the actor Akhil Akkineni (born 1994).

In 1988, he starred in the blockbuster Aakhari Poratam, scripted by Yandamuri Veerendranath, and directed by K. Raghavendra Rao where he was paired opposite Sridevi and Suhasini. In 1988 he starred in Janaki Ramudu paired with Vijayashanti. This film, directed again by K. Raghavendra Rao, was also a decent Runner. Though his acting was not up to the standards, he was lucky enough to get more opportunities.

In 1989 he starred in the Maniratnam-directed romantic drama Geetanjali. The film went on to win the National Film Award for Best Popular Film Providing Wholesome Entertainment in 1990.

Immediately, he saw another success, Siva. This film marked the debut of leading Bollywood Director Ram Gopal Varma. The film is based on college politics, a new genre at that time. In 1990, he subsequently made his Bollywood debut with the Hindi remake of the same film titled Shiva. Even the Hindi version saw a huge box-office success. He then starred in the social Problem film Jaitra Yatra, for which he received critical reception. He followed it up with average fare like Prema Yuddham, Nirnayam and Iddharu Iddhare. All these films did nothing exceptional to Nagarjuna's career as they were only moderately acclaimed and saw only average success.

In 1994 he starred in the Hindi-Telugu bilingual Criminal directed by Mahesh Bhatt. In the same year he ventured into comedy for the first time with Hello Brother. This was later remade into Hindi as Judwaa and dubbed into Tamil. In 1996, Nagarjuna starred and produced Ninne Pelladata, which was directed by Krishna Vamsi. The movie won the National Film Award for Best Feature Film in Telugu and Filmfare Award for Best Film - Telugu. The next year, Nagarjuna acted in Annamayya, in which he portrayed the role of Annamacharya, a 15th-century Telugu singer and poet. This won him his Filmfare Best Actor Award and his first Nandi Award for Best Actor. He also received a National Award for Special Mention for the film Annamayya. His subsequent releases were Nuvvu Vastavani, Ninne Premistha and Azad.

Known for his works in biographical films, He essayed 15th-century Composer Annamacharya in the 1997 film Annamayya; as Yavakri (the son of the ascetic Bharadwaja) in the 2002 film Agni Varsha; as Major Padmapani Acharya in the 2003 war film LOC Kargil; as 17th-century Composer Kancherla Gopanna in the 2006 film Sri Ramadasu; as Suddala Hanmanthu, in the 2011 film Rajanna; as Sai Baba of Shirdi in the 2012 film Shirdi Sai; as Chandala in the 2013 film Jagadguru Adi Sankara, and as Hathiram Bhavaji in the 2017 film Om Namo Venkatesaya.

He starred in romantic comedies such as Santosham, Manmadhudu, and Shivamani. He produced Satyam in 2003, which starred his nephew Sumanth. In 2004, Nagarjuna had two releases, Nenunnanu and Mass. The latter was produced by Nagarjuna and directed by Choreographer Lawrence Raghavendra. In 2005, Nagarjuna acted in and produced Super. In 2006, he starred in Sri Ramadasu, his second period film based on the 18th-century Telugu Composer of the same name. Nagarjuna received the Nandi Award for Best Actor for the film. In December 2007, he appeared in Don and a year later, he appeared in King alongside Trisha Krishnan and Srihari.

Nagarjuna, with his wife Amala, are the co-founders of Blue Cross of Hyderabad, a registered society recognized by the Animal Welfare Board of India. It is a non-government organization (NGO) in Hyderabad, which works towards the welfare of animals and preservation of animal rights. Nagarjuna is also involved in welfare programs undertaken by the MAA TV association, and serves as the brand ambassador for HIV/AIDS awareness campaigns. In 2010, he starred in an HIV/AIDS animated software tutorial created by TeachAIDS, a nonprofit founded at Stanford University.

In 2010, he had releases ibcluding Kedi and Ragada. Gaganam was released on 11 February 2011. Its Tamil version was titled Payanam. In 2011 Nagarjuna signed three movies in a row: Rajanna, Damarukam and Shirdi Sai. He completed two new films, including Greekuveerudu, starring Nayanatara opposite him, which was an average grosser at the box office. His next release was Bhai, which was a disaster at the box office, and which starred Richa Gandhopadhyay opposite to him. In 2014, Nagarjuna starred in the blockbuster family drama, Manam, directed by Vikram Kumar. He had a dual role in Soggade Chinni Nayana, and later he played a handicapped person in Vamshi bilingual film Oopiri, a blockbuster hit.

As of 2013, He is the co-owner of Mumbai Masters of the Indian Badminton League, along with Sunil Gavaskar, and Mahi Racing Team India, along with Mahendra Singh Dhoni. Nagarjuna currently endorses Kalyan Jewellers in Telangana and Andhra Pradesh. He is listed #56 and #61 in Forbes India's top 100 Celebrities for the years 2012 and 2013 respectively.

Nagarjuna is the founding partner of N3 Realty Enterprises, the parent entity for N-Convention center, N-Grill and District N in Hyderabad, which is jointly owned by himself and Nalla Preetham Reddy. In 2014, the Greater Hyderabad Municipal Corporation identified that the convention facility had encroached upon the Full Tank Level boundary. Subsequently, through legal opinions sought by Nagarjuna, a correction path of the land has been initiated by the local administrators.

In December 2016, at a private ceremony held in Hyderabad, Nagarjuna's younger son Akhil Akkineni got engaged to marry Shriya Bhupal, granddaughter of Business magnate GV Krishna Reddy, founder of the GVK group of companies.