Priyamani is an established actress in the South Indian film industry. She grew up in Bangalore, completed her schooling at Sri Aurobindo Memorial School and later went to Bishop Cotton Woman's College.

Right from student life, Priyamani was enthusiastic about extracurricular activities. As a student, she took part in a lot of competitions. She began working as a model for Kanchipuram silks after completing her studies.

During her college years, she began modelling and appeared in several advertisements, which eventually led to her foray into the film industry.

She was soon spotted by Bharathiraja in 2003, who offered her a role in the Tamil film Kangalal Kaidhu Sei (2004). However, it is the Telugu film Evare Athagadu (2003) that is considered her debut film as it came out first.

After her debut, she appeared in several other South Indian films and made a name for herself with her performances in films like Sathyam (2004), Athu Oru Kanaa Kaalam (2005), and Pellaina Kothalo (2006).

Priyamani's breakthrough performance came with the Tamil film Paruthiveeran (2007), directed by Ameer Sultan. She played the role of a village girl, and her portrayal of the character won her several awards, including a National Film Award and a Tamil Filmfare award for Best Actress.

After winning the National Award, the actress went on to give a noteworthy performance in the commercially successful Telugu film, Thief of Yama (2007), directed by S.S. Rajamouli.

In 2008, Priyamani received praise for her performance in the Malayalam film Thirakkatha (2008). This movie's plot revolves around twists and turns of the real-life lived by the late film actress Srividya. She also starred in the critically acclaimed and successful Tamil film Thotta (2008).

In 2009, Priyamani appeared in the successful remake of Ninaithale Inikkum (2009) and made her Kannada film debut with the successful Raam (2009).

In 2010, Priyamani starred in the super hit Pranchiyettan and the Saint (2010) with Mammootty. She played a Mumbai interior designer, and the film grossed over four crores in a little over two weeks.

Priyamani then worked with director Mani Ratnam on Raavanan (2010) and Raavan (2010), which was a hit in Tamil but a box-office disaster in Hindi.

She later acted in Ram Gopal Varma's Rakta Charitra (2010) with Vivek Oberoi, Suriya, and Shatrughan Sinha. The movie was critically acclaimed, and a box-office hit.

In 2012, Priyamani received critical acclaim for her roles in Anna Bond (2012) and Grandmaster (2012). She also starred in the superhit Kannada film Chaarulatha (2012) and won multiple awards, including Kannada Filmfare, for her portrayal of conjoined twins.

In 2013, she starred in the commercially and critically successful Telugu film Chandi (2013).

In 2016, she appeared in Kathe Chitrakathe Nirdeshana Puttanna (2016), a comedy horror film that had a successful 50-day run. She then starred in the romantic comedy Dana Kayonu (2016) directed by Yograj Bhat.

In 2017, she starred in the horror film Kalpana 2 (2016), directed by R. Anantharaju.

On August 23, 2017, Priyamani married her long-time boyfriend, Mustafa Raj, a businessman, in a private ceremony in Bangalore. It was rumoured that Priyamani planned to retire from acting after the wedding, but these reports were proven incorrect when she starred in the film Dhwaja (2018).

Having established herself in the South Indian film industry, Priyamani is now making waves with her performances in web shows. Her portrayal of the character "Suchitra Iyer" in her debut web series, The Family Man (2019), fetched her the Filmfare OTT award for Best Actress in a Drama Series (Critics).

Besides The Family man, her on-screen performance of the character Sakshi in ZEE5's His Story (2021) has moved audiences with her acting skills.

Priyamani has also appeared as a judge in many dance reality shows like the Telugu dance shows Dhee (2013) and the Tamil show Dance jodi dance 2.0 (2017).