In the same year, he appeared in the commercially successful Siva, an action film directed by Ram Gopal Varma; featured at the 13th IFFI' 90.

Known by his works in biographical films, he played 15th-century composer Annamacharya in Annamayya (1997), Yavakri (the son of the ascetic Bharadvaja) in Agni Varsha (2002), Major Padmapani Acharya in the war film LOC: Kargil (2003), 17th-century composer Kancherla Gopanna in Sri Ramadasu (2006), Suddala Hanmanthu in Rajanna (2011), Sai Baba of Shirdi in Shirdi Sai (2012), Chandaludu in Jagadguru Adi Shankara (2013), and Hathiram Bhavaji in Om Namo Venkatesaya (2017).

[9] Nagarjuna has largely starred in action films, establishing himself as an action star with works such as Aakhari Poratam (1988), Vicky Daada (1989), Siva (1989), Neti Siddhartha (1990), Chaitanya (1991), Nirnayam (1991), Antham (1992), Killer (1992), Khuda Gawah (1992), Rakshana (1993), Hello Brother (1994), Govinda Govinda (1994), Criminal (1994), Ratchagan (1997), Azad (2000), Sivamani (2003), Mass (2004), Super (2005), Don (2007), and King (2008).

[21] Years later he made his debut as a lead actor through the 1986 Telugu film Vikram, directed by V. Madhusudhana Rao.

He then starred in Sankeertana, a below average grosser directed by debutant Geetha Krishna with music by Ilaiyaraaja.

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.

[25] In 1990, he subsequently made his Bollywood debut with the Hindi remake of the same film titled Shiva.

[26] He followed it up with box office hits like Nirnayam (1991), Killer (1992) and working with eminent directors such as Fazil and Priyadarshan.

[27] Some of his prominent hit films released subsequently included President Gari Pellam (1992), Varasudu (1993), Allari Alludu (1993), Hello Brother (1994) and Gharana Bullodu (1995).

In 1996, Nagarjuna starred opposite actress Tabu and produced Ninne Pelladata, directed by Krishna Vamsi.

[28] The next year, Nagarjuna acted in Annamayya (1997), in which he portrayed the role of Annamacharya, a 15th-century Telugu singer and poet.

[31] In 1998, he appeared in the romantic comedy Aavida Maa Aavide and then plays as lead role in the Hindi action Angaaray with Akshay Kumar.

[36][37] His subsequent releases were Tamil remakes Nuvvu Vastavani (2000), Ninne Premistha (2000) and Snehamante Idera (2001).

[55] He then starred in a horror film titled Raju Gari Gadhi 2 (2017), which had an average run at the box office.

[69] Since 2013, He was a co-owner of the Mumbai Masters of the Indian Badminton League, along with Sunil Gavaskar, and the Mahi Racing Team India, along with MS Dhoni.

[74] Nagarjuna is the founding partner of N3 Realty Enterprises, the parent entity for N-Convention center, N-Grill and District N. The later two establishments are now non-existent.

[76] On 24 August 2024, the Hyderabad Disaster Response and Asset Monitoring and Protection (HYDRAA) demolished the N-Convention centre citing encroachment of adjacent lake.

[77] Nagarjuna, along with his wife Amala, are co-founders of Blue Cross of Hyderabad, recognised by the Animal Welfare Board of India.

Nagarjuna was also involved in welfare programs undertaken by the MAA TV association, and presently serves as the brand ambassador for HIV/AIDS awareness campaigns.

[80] In 2010, he starred in an HIV/AIDS animated software tutorial created by TeachAids, a nonprofit founded at Stanford University.

[81] In February 1984, Nagarjuna married Lakshmi Daggubati, the daughter of D. Ramanaidu, a prominent film-maker, and sister of the actor Venkatesh and producer Suresh Babu.

Nagarjuna then married actress Amala on 11 June 1992,[84] and the couple have one son, actor Akhil, born on 8 April 1994.