After graduating with a degree in commerce from Sri Y N College at Narsapur, Chiranjeevi moved to Chennai and joined the Madras Film Institute in 1976 to pursue a career in acting.

In a remake of the Tamil film Avargal, Chiranjeevi portrayed the character played by Rajinikanth in the original. In 1979, Chiranjeevi had eight major film releases and then 14 films in the following year. He played lead antagonist in works such as Mosagadu, Rani Kasula Rangamma, 47 Natkal /47 Rojulu, Nyayam Kavali and Ranuva Veeran.

On 20 February 1980, Chiranjeevi married Surekha, the daughter of Telugu comic actor Allu Ramalingaiah. They have two daughters, Sushmita and Srija, and a son, Ram Charan, also an actor in Telugu cinema.

Khaidi was a box office success and Chiranjeevi attained stardom with this movie. In 1984, he continued doing action films. A series of box office hits at this time include; Mantri Gari Viyyankudu, Sangharshana, Goonda, Challenge, Hero, Donga, Jwala, Adavi Donga, Kondaveeti Raja, Rakshasudu, Gang Leader, Rowdy Alludu, Yamudiki Mogudu and Donga Mogudu. In 1985, he received his second Filmfare Award for Best Actor – Telugu for his performance in Vijetha. Chiranjeevi received his first Nandi Award for Best Actor for Swayam Krushi (1987), directed by K. Viswanath.

Chiranjeevi’s Bollywood performances were appreciated in Pratibandh (1990) and Aaj Ka Goonda Raj. In 1996, he appeared in a guest role in the Kannada film Sipaayi. For his role in Aapadbandhavudu (1992), he received his second Nandi Award for Best Actor and third Filmfare Award for Best Actor – Telugu. The mid-1990s saw a career dip for Chiranjeevi with box office duds such as Mechanic Alludu, S. P. Parasuram, Big Boss and Rikshavodu. There were exceptions, such as Mutha Mestri, which fetched him a fourth Filmfare Award for Best Actor – Telugu, Mugguru Monagallu and Alluda Majaka were moderately successful. After a brief lull, Chiranjeevi bounced back with Hitler, Master, Bavagaru Bagunnara?, Choodalani Vundi and Sneham Kosam, for which he received his fifth Filmfare Award for Best Actor – Telugu. In 1999, Chiranjeevi was to appear in a Hollywood production directed by Dushan Garsi, and produced by Rameshkrishna Murthi. The Telugu version was directed by Suresh Krissna. The movie, which was titled The Return of the Thief of Baghdad, had its filming suspended for undisclosed reasons.

On 2 October 1998, he founded the Chiranjeevi Charitable Trust (CCT), which includes Chiranjeevi Blood and Eye Banks. It is the state’s largest recipient of blood and eye donations. The trust has made over 68,000 blood donations and 1,414 eye donations. The Blood Bank of the CCT has helped over 80,000 people and the Eye Bank has helped about 1,000 people in the state of Andhra Pradesh since its opening. Around 350,000 people have pledged their eyes to CCT so far, giving 1600 people eyesight through CCT. CCT has also won the “Best Voluntary Blood Bank Award” by the AP State Government for the past 4 years. On 10 June 2006, the then President of India, Abdul Kalam, inaugurated the Chiranjeevi Charitable Foundation (CCF) at the Jubilee Hills Check Post in Hyderabad.

Chiranjeevi’s new decade started with Annayya. After a brief gap, Chiranjeevi starred in Indra, released in 2002, which broke all his previous box office records of Tollywood and won him his third Nandi Award for Best Actor and sixth Filmfare Award for Best Actor – Telugu. After that, he appeared in films with an underlying message and a social cause, including Tagore and Shankar Dada MBBS, for which he won his seventh and latest Filmfare Award for Best Actor – Telugu, and Stalin. He was awarded the Filmfare Special Award – South in 2006 and the Filmfare Lifetime Achievement Award – South at the 58th Filmfare Awards South in 2011 for his contributions to the film industry.

In 2008, Chiranjeevi started Praja Rajyam, a political party in the state of Andhra Pradesh. At the launch, he stated that social justice was the main agenda of his party. In the 2009 general elections, the party won 18 of the 295 seats in the Andhra Pradesh State Assembly. He was elected a Member of the State Assembly from Tirupati.

Following his last film in the lead role, 2007’s Shankar Dada Zindabad, Chiranjeevi did not star in any film for approximately 10 years, during which he embarked on his political career. During these 10 years, his appearances in films was limited to cameos films. He appeared as himself in two film, starring his son Ram Charan, namely Magadheera in 2009 and Bruce Lee – The Fighter in 2015. He also narrated Varudu (2010) and Rudhramadevi (2015), including a cameo in Jagadguru Adi Shankara (2013) where he reprised his role as Lord Manjunatha from Sri Manjunatha (2001).

He contested from both Tirupati and Palakollu Constituencies for MLA in the 2009 general elections, winning in Tirupati but losing out in Palakollu, in West-Godavari district.

On 6 February 2011, Chiranjeevi merged the 30-month-old Praja Rajyam Party with the Indian National Congress, after two weeks of talks with Sonia Gandhi, the president of the Congress, which feared the no-confidence motion in the state assembly in the wake of the emergence of Jagan Mohan Reddy’s YSR Congress Party and the stronghold of Telangana agitation. After more than one year of merging his party into Congress, he was nominated to Rajya Sabha on 29 March 2012. He got elected and took the oath as a Rajya Sabha member on 3 April 2012. On 28 October 2012, he was sworn in as the Union Minister of State (Independent charge), Ministry of Tourism, Government of India.

From 2013 onwards, he was on the lookout for the right script to mark his comeback into cinema, in what would coincidentally happen to be his 150th film as an actor. A year following the release of the highly successful 2014 Tamil film Kaththi, Chiranjeevi chose to remake that film in Telugu as his comeback film. The remake, titled Khaidi No. 150, directed by V. V. Vinayak, was released during the Sankranti holiday in 2017, about 6 months short of a decade following Shankar Dada Zindabad, to positive reviews. Critics have singled out Chiranjeevi in particular, praising him for both his performance and appearance, especially following a decade of absence from cinema. Khaidi No. 150 collected to ₹41.75 crore on its opening day and grossed ₹164 crore in its lifetime. In 2019, he starred in his first period film Sye Raa Narasimha Reddy based on the life of Uyyalawada Narasimha Reddy and directed by Surender Reddy. Sye Raa, made on a budget more than ₹200 crore, grossed more than ₹240 crore in its theatrical run. Chiranjeevi’s upcoming film Acharya is directed by Koratala Siva.

After the Indian National Congress split the state of Andhra Pradesh leaving the residuary state with huge debt and little revenue in June 2014, most members of the Andhra Pradesh wing of Indian National Congress party left in protest. Chiranjeevi, however, remained with Indian National Congress and did a campaign for Indian National Congress as chairman of election campaign committee for 2014 parliamentary and assembly elections in the residuary state of Andhra Pradesh, however, he refrained from contesting in elections. There was also criticism that he did not campaign wholeheartedly due to the one-sided decision was taken to split Andhra Pradesh. His youngest brother Pawan Kalyan, a former Praja Rajyam Party youth wing leader, launched his own political party Jana Sena and campaigned vigorously against Indian National Congress and in favor of Telugu Desam Party and Bharatiya Janata Party. Due to the strong anti-Indian National Congress sentiment prevailing in Andhra Pradesh, its candidates were defeated in all parliamentary and state assembly seats Andhra Pradesh with 165 out of 175 candidates losing deposit [obtaining less than 10% of vote share]. Since the 2014 elections, he has maintained distance from active politics and will also end his tenure as Rajya Sabha member in April 2018. He has not attended any sessions of Indian National Congress either.

Director K. Balachander said “Chiranjeevi has both Kamal Haasan and Rajinikanth in him. Not only can he do action, he can also act.” Chiranjeevi received the Padma Bhushan, the third highest civilian honour in India in the year 2006. He was awarded an Honorary Doctorate by Andhra University in the same year. He is a ten-time winner of Filmfare Awards South and a four-time winner of Nandi Awards. In 2014, he was awarded International Face of Indian Cinema at the 3rd South Indian International Movie Awards from Tengku Adnan Tengku Mansor. He was the first actor from South India to be invited to the Oscars ceremony in 1987.

Chiranjeevi made his debut as Television host with the fourth season of Meelo Evaru Koteeswarudu. The first episode of fourth season was aired on 13 February 2017. The game show, a Telugu version of Kaun Banega Crorepati, was telecasted Monday to Thursday at 9.30 pm.