Asin's first assignment was an advertisement for BPL Mobile. She debuted in the Malayalam film Narendran Makan Jayakanthan Vaka in 2001, at the age of 15. After taking a year out to pursue her education, Asin returned with her breakthrough film as an Actress, Amma Nanna O Tamila Ammayi opposite Ravi Teja, portraying a Tamil girl in her first Telugu language film, which subsequently fetched her the Telugu Filmfare Award for Best Actress. In the same year she won the Santosham Best Actress Award for her performance alongside Akkineni Nagarjuna in her second Telugu film Shivamani. Her following two Telugu films Lakshmi Narasimha and Gharshana, both portrayed Asin as the love interest for police officers and both were successful ventures.

Asin has been the brand ambassador for several companies and products, and has appeared in commercials for Avon, Mirinda, Colgate, Fairever, Tanishq, Big Bazaar, Parachute, Spinz talc, Lux, Amrutanjan Health care, and Clinic All Clear. Asin has been endorsing Mirinda soft drinks since 2004.

After the release of Ullam Ketkumae, Asin was cited as a leading heroine of the Tamil film industry after starring in blockbuster films such as Ghajini, Sivakasi, Varalaru and Pokkiri respectively. The film which provided the breakthrough for Asin was Ghajini. The film, co-starring Surya, directed by A.R. Murugadoss, earned her the Tamil Filmfare Award for Best Actress. Her role was that of a vivacious young model named Kalpana. Sify.com praised her portrayal as "magical", describing her character as a "lovable chatterbox", played with "sheer ability in the romantic interludes, the poignant and heartfelt scenes when she rescues minor girls from villains and her gory end are touching". On the following Diwali in 2005, Asin had two releases, Sivakasi and Majaa. Despite the latter becoming an average grosser, the former went on to be a successful venture at the box office.

Asin appeared in her first dual role in K. S. Ravikumar's Dasavathaaram opposite Kamal Haasan, who portrayed ten roles. The film had been under production since September 2006. Despite being overshadowed by Haasan's ten roles, Asin's portrayals in the film were praised as her "best-to-date", with one of her roles being that of a Vaishnavite in 12th century Tamil Nadu; whilst the other character was a Brahmin girl from Chidambaram, for which she won her first ITFA Best Actress Award. Dasavathaaram subsequently went on to become one of the blockbusters.

The following year, her long-delayed venture Varalaru opposite Ajith Kumar also succeeded at the box office, and The Hindu said she "looks lustrous and sails through her role smoothly". Asin appeared in Pawan Kalyan's Annavaram, another successful venture, which was a remake of Thirupaachi. In January 2007, Asin appeared opposite Ajith Kumar and Vijay in two different films, Aalwar and Pokkiri, with the latter becoming a success, whilst Aalwar became a failure. Though Asin's role in Aalwar was criticised, her performance in Pokkiri was lauded by critics. Her final project of the year was opposite Surya, in Hari's Vel, which had a Diwali 2007 release, subsequently becoming her third successful film which released during the Diwali season in three years. Asin, who portrayed a TV anchor, was appreciated for her role in the film.

Ghajini became the highest grossing Bollywood film of 2008 and the sixth highest-grossing Bollywood film of all time according to net collections. Asin later appeared in Vipul Shah's London Dreams, alongside Salman Khan and Ajay Devgn, in which she played a south Indian girl, Priya, who is emotional but strong willed and an ambitious Dancer at the same time. The film received mixed reviews from critics.

Her next movie with Salman Khan, Ready, was released on 3 June 2011 to mixed reviews. Critics praised the chemistry between Salman and Asin. Upon release, Ready became the second highest weekend grossing Bollywood film, after Dabangg and went on to become the fifth film in Bollywood history to cross the coveted ₹1 billion (US$15 million) mark in the domestic market.

In an interview during the DNA I Can Women's Half Marathon in 2012, Asin, speaking about the importance of health and the necessity of education said:

Asin currently resides in Mumbai. She also owns an apartment in Marine Drive, Kochi and a farmhouse in Vagamon, Kerala. The Actress is a polyglot. She can speak seven languages; being well-versed in Malayalam (her mother tongue), Tamil, Telugu, Sanskrit, English, Hindi and French. Asin also speaks a smattering of Italian and learnt basic Marathi for her movie Khiladi 786, in which she played a typical Marathi girl. In June 2013, it was reported in the Indian media that Asin was learning German during her free time. She began learning Spanish after visiting Spain in early 2014.

Asin married Micromax co-founder Rahul Sharma in January 2016, and quit acting after the wedding. Her first child was born on October 24, 2017.