In the 1960s, the crime drama Gunga Jumna (1961) saw Vyjayanthimala playing a rustic village belle, Dhanno, a role which won her the Filmfare Award for Best Actress.

She was born in Chennai : Triplicane near Parthasarathy Temple in a Tamil Iyengar Brahmin family to Mandyam Dhati Raman and Vasundhara Devi.

[4] At the age of 7, Vyjayanthimala was chosen to perform a classical Indian dance for Pope Pius XII while her mother was an audience in 1940 at Vatican City.

In the late 1950s, Vyjayanthimala was linked by gossip magazines with Dilip Kumar, who has acted with her the most compared to any other actress, which resulted in great on-screen chemistry between them.

[8] In February 2024, at age 90, she took part in Raag Sewa performance series at Ram Mandir, Ayodhya, with a Bharatnatyam dance recital, and its video soon became viral on social media.

[6] Vyjayanthimala barely at 13 played a college girl named Mohana Shivashankaralingam and acted along with senior actors S. V. Sahasranamam, M. S. Draupadi, T. R. Ramachandran and K. Sankarapani.

In their first Hindi venture, they decided to cast Vyjayanthimala again in the lead role with Karan Dewan, Om Prakash and Pandari Bai (who was credited as Padmini in the film).

Her dancing, too, is very graceful, specially in those eye-filling colour sequences and delightful ballets towards the finish", while in The Hindu review Vijay Lokapally similarly praised her portrayal: "The ethereal Vyjayanthimala, barely 18, illuminates the screen with her stunning beauty, moving around daintily from one song to the other...

The same year, Bimal Roy cast her as Chandramukhi opposite Dilip Kumar in the critically acclaimed Devdas, which was the adaptation of the novel with same title by Sharat Chandra Chatterji.

The industry initially was not in favour of this choice when they heard about Vyjayanthimala being cast in Bimal Roy's film, the response being: "Why don't you take comedian Kishore Kumar as Devdas?".

[36] After being recognised as a capable actress with Devdas, Vyjayanthimala acted in successful movies in 1956, namely Taj, Patrani and Anjaan: Somewhere in Delhi – all three films with Pradeep Kumar as the hero and Kismet Ka Khel with Sunil Dutt.

The new film, Naya Daur, had a theme of "Man vs. machine", and Vyjanthi's portrayal of village belle Rajni received positive reviews from critics.

She ably projects a hands-on worker who comes up with ideas on how to ford a stream and risks her life to save the bridge... wonderful scene between two stars whose chemistry is undeniable"[44] while reviewer Taran Adarsh from Bollywood Hungama mentions that: "Commendable performances come in from Vyjayantimala [natural]...The relationships [Dilip Kumar-Vyjayantimala] are so human and believable".

[56] During the filming in the hills of Nainital, Vyjayanthimala was required to dance barefoot where she tripped on a stone and fell, hurting herself badly and causing damage to her fibre tissues in the sole of her foot.

[67] The Filmfare award-winning story by Mukhram Sharma revolves around Rajini, enacted by Vyjayanthimala, a prostitute's love affair with a professor, played by Sunil Dutt.

[69] Along with the film, her performance received universal acclaim, as told by Vijay Lokapally from The Hindu: "Among the great movies made on the subject of helpless women versus society, Sadhna holds its own for its realistic portrayal and treatment of a subject, so aesthetically documented by Chopra and Vyjayanthimala" and praised the latter "gorgeous when she entertains the clients at her kotha...stunningly restrained when she assumes the character of a prospective wife".

[78] One of the first screen adaptations of Kalki Krishnamurthy's Ponniyin Selvan, the film had a huge ensemble cast consisting of Savitri, Gemini Ganesan, Padmini, Saroja Devi, M. N. Rajam and Nagesh along with Ramachandran and Vyjayanthimala.

In this dacoit drama, she enacted the role of Dhanno, a washerwoman who falls for childhood friend Gunga, played by Kumar and eventually killed during a gun fight.

[108] For her portrayal, Vyjayanthimala got some negative feedback from the critics; The Hindu review said that: "Even the otherwise powerhouse of talent, Vyjayantimala, with many a sterling performance under her belt, barely passes muster, despite the usual dance and song sequence to showcase her formidable prowess as an accomplished dancer thrown in".

The same year Bimal Roy who earlier worked with her in Devdas and Madhumati offered her the lead role in Bandini opposite Ashok Kumar and Dharmendra.

Dinesh Raheja of Rediff said that: "to put it simply, radiant...the maturity with which she tackles her character, the insouciance as well as the agony" and called it "one of commercial cinema's most unforgettable performances".

[128] Zindagi became a success at the box office, where it celebrated a silver jubilee theatrical run and was the fourth highest-grossing film of that year with a verdict of "hit".

[130] In 1965, Vyjayanthimala starred in two commercial disappointments; Naya Kanoon, with Ashok Kumar and Bharat Bhushan and Nam Iruvar with T. R. Mahalingam, but both the films are considered masterpieces by critics.

The film was a colossal disaster at the box-offie, which left Vyjayanthimala heartbroken, where she decided to quit the industry, though director Baldev Raj Chopra felt that she could have easily continued for another decade in lead roles.

[139][140] The same year she did the magnum opus Chhoti Si Mulaqat, produced by the legendary Bengali actor and matinee idol Mahanayak Uttam Kumar.

A remake of the 1954 Bengali film Agni Pariksha, which had Uttam Kumar, who reprises his role in the Hindi version and Suchitra Sen in the lead.

[143] Similarly, her singing in the song "Shyam Tor Tore Tamal Tolay Boshe Thaki" along with singer Hemanta Mukherjee received praise, where it was described as a "pleasant surprise" in the same review.

[149] In 1969, she was the first Indian dancer to perform at the United Nations General Assembly to commemorate the 21st anniversary of the proclamation of the Universal Declaration of Human Rights.

In 1968, she was signed opposite Raj Kapoor in Mahesh Kaul's Sapno Ka Saudagar, she refused the role which went to the debutante Hema Malini, who become one of the most popular actresses in Hindi films later.

Vyjayanthimala's political career was initiated in 1984 when she contested in 1984 Tamil Nadu general election for the South Chennai constituency as the nominee of the Indian National Congress opposite Era Sezhiyan, the leader of Janata Party and seasoned parliamentarian.