Krishnan was born to Tamil parents, Krishnan and Uma Krishnan, in Chennai, Tamil Nadu. She attended M.S.E.C College in Ramnad and later studied at Sacred Heart Church Park School, Chennai. In school, she participated in several cultural activities, sports and school band. While studying in M.S.E.C college, she ventured into part-time modeling and participated in various beauty pageants. She converses fluently in Tamil, Telugu, Hindi & English. As part of her modeling career, she appeared in many TV advertisements including that of Fanta, Tata Indicom and Vivel ITC. She also appeared in Falguni Pathak's music video Meri Chunar Ud Ud Jaye as Ayesha Takia's friend dancing in the video.

Soon after her pageant success, Krishnan began her career acting in an uncredited role as Simran's friend in Jodi before moving onto appear in advertisements and in music videos, with Falguni Pathak's Meri Chunar Ud Ud Jaye being the most prominent. The first project she accepted was the Priyadarshan-directed Lesa Lesa, with the promotional posters for the film, also creating an offer to star in the A. R. Rahman musical, Enakku 20 Unakku 18 (2003).[7] However both the projects' releases were severely delayed, and her first release was Ameer's Mounam Pesiyadhe opposite Surya Sivakumar. The film became a moderate success at the box office and did manage to gain credentials for Trisha, with critics claiming that she was "undoubtedly a refreshing new find, with sparkling eyes and appealing demeanour", also going onto praise the dubbing artiste, Savitha Reddy, who has since regularly dubbed for Trisha.[8] Manasellam, her second project, saw her play a cancer patient; but the film also went unnoticed despite positive reviews for the film and the actress.[9]
However her next release in 2003, the Hari-directed police film, Saamy with Vikram, became a blockbuster at the box office, landing her new offers. In 2004, she debuted in the Telugu cinema industry with Varsham, which went on to become the highest-grosser of the year and turned her into an overnight sensation. Later that year, she was part of another commercially successful Tamil venture, Ghilli. In 2005, she starred alongside Siddharth Narayan in the Telugu flick Nuvvostanante Nenoddantana as the village girl Siri. The film is about a rich boy, who tries to marry a girl - however her brother opposes. Directed by Prabhu Deva, it was successful at the box office,[10] and Krishnan won two awards for the film which include the Filmfare Award and Nandi Award.[11]
She next appeared in Mani Ratnam's political drama Aayutha Ezhuthu, starring as part of an ensemble cast that included Siddharth Narayan, Madhavan and Surya. Her subsequent releases, N. Lingusamy's Jiand the Vijay-starrer Aathi did not do well at the box office, while Aaru was a success and was received well by critics.[12] Her 2006 Telugu film, Pournami, directed by Prabhu Deva, was a flop. However, another 2006 film, Something Something ... Unnakum Ennakum, where Krishnan acted opposite Jayam Ravi, did well at the box office. The film was a remake of the Telugu film, Nuvvostanante Nenoddantana, where she essayed the same role.
She starred in the Telugu film Stalin with Chiranjeevi, following which her Telugu film Sainikudu with Mahesh Babu was released. Her next release was Aadavari Matalaku Ardhalu Verule where she was cast opposite Venkatesh. The film, Selvaraghavan's first Telugu venture, was a family entertainer and received good response especially from the family audience. Krishnan's performance was critically acclaimed and won her accolades, eventually resulting in her third Filmfare win.
In Kireedam with Ajith Kumar, Krishnan tried comedy and received rave reviews. Kireedam opened with high expectations and received good reviews from media and audience and was declared a success. Her 2008 films, Bheema and Kuruvi failed to succeed at the box-office, whilst Krishna with Ravi Teja, opened to rave reviews, and became a blockbuster. Her other release Bujjigadu starring Prabhas, directed by Puri Jagannadh was released during Summer and made a decent run. However Radhamohan's Abhiyum Naanum became a super hit and Krishnan was praised for her performance. King starring Akkineni Nagarjuna directed by Sreenu Vaitla was a December release and it became a blockbuster.
In 2009 her movie Sarvam with Arya did not do well and became just an average grosser. Her latest Tamil release Vinnaithaandi Varuvaayaa, directed by Gautham Menon opposite Silambarasan, released to positive reviews and also became a commercial success. Her 2010 Telugu release Namo Venkatesa, opposite Venkatesh, is a super hit. Krishnan is now starring in Manmadhan Ambu with Kamal Haasan and R. Madhavan. Trisha made her debut in Hindi film industry with the Priyadarshan film Khatta Meetha, starring opposite Akshay Kumar.
Krishnan recently replaced Rani Mukherjee as the Brand Ambassador of Fanta India.[3] She is the brand ambassador of Scooty Pep+, for which she has replaced Preity Zinta. She is also the brand ambassador for Vivel Di Wills, a product by ITC.