Her mother persuaded her to work in films when Jayalalitha was still in school, taking assurances from producers that shooting would take place only during summer vacations and that she would not miss her classes. Jayalalitha acted in an English language film, Epistle, released in 1961. She made her debut as the lead actress in Kannada films while still in school, aged 15, in Chinnada Gombe (1964).
Between 1965 and 1972 she acted frequently with M. G. Ramachandran and she also worked with B. Saroja Devi in Arasa Kattali. Her other early roles were in suspense films such as Naan and comedies such as Galatta Kalyanam.
In 1972, Jayalalithaa acted in Pattikada Pattanama opposite Sivaji Ganesan, which won the National Film Award for Best Feature Film in Tamil. The film also won her a Filmfare Award for Best Actress – Tamil. She was the first recipient of Filmfare Award for Best Actress – Tamil and Filmfare Award for Best Actress – Telugu when the categories were introduced in 1972. Her performance in Suryakanthi and Chandradhoyam were critically acclaimed and the former won her another Filmfare Award for Best Actress – Tamil in 1973.
Her other films with Sivaji Ganesan include Galatta Kalyanam and Deiva Magan. Deiva Magan also holds the distinction of being the first ever Tamil film to be submitted by India in contest for the Academy Award for Best Foreign Language Film. She continued pairing up with younger actors such as Ravichandran and Jaishankar in a number of films such as Vairam, Baghdad Perazhagi.
Later Tamil films in which she acted included Kandan Karunai and she also starred in Bollywood films, initially in Izzat, which saw her paired with Dharmendra. She also established her popularity in Telugu films, including Sri Krishna Satya. Her last film was Nadhiyai Thedi Vandha Kadal which released in 1980.
Her involvement in politics grew from her association with Ramachandran, who had founded the AIADMK and was Chief Minister of Tamil Nadu as well as an actor, In 1980 he made Jayalalithaa the party's Propaganda Secretary. She was nominated to the Rajya Sabha in 1984.and her position as Ramachandran's political disciple helped her become his political heir.After the death of Ramachandran she was alienated by a faction of the party who chose to support his wife, Janaki Ramachandran.
Due to an anti-incumbency wave, and several allegations of corruption and malfeasance against her and her ministers, she lost power to the D.M.K in 1996, in a landslide defeat. All the ministers in her erstwhile cabinet, including her, were defeated in the elections and six of them lost their deposits, meaning that they did not even secure the minimum number of votes expected of them.
She returned to power with a huge majority in the 2001 elections, having mustered a bigger coalition and defying many pre-poll predictions. In the 2006 assembly elections, her party lost to the DMK