Nayanthara made her acting debut in the 2003 Malayalam film Manassinakkare with Jayaram. She made her debut in Tamil cinema with Ayya (2005) and Telugu with Lakshmi (2006). Both were successful. After this she had numerous commercially successful Tamil and Telugu films like Chandramukhi (2005), Dubai Seenu (2007), Tulasi (2007), Billa (2007), Yaaradi Nee Mohini (2008), Aadhavan (2009), Adhurs (2010), Simha (2010), Boss Engira Bhaskaran (2010), Sri Rama Rajyam (2011), Raja Rani (2013), Arrambam (2013), Thani Oruvan (2015), Maya (2015), Naanum Rowdy Dhaan (2015), Babu Bangaram (2016) and Iru Mugan (2016).
In 2010, she also made her Kannada film debut through the Kannada-Telugu bilingual film Super, her only appearance in a Kannada film to date. Her portrayal of Sita in Sri Rama Rajyam (2011) earned her the Filmfare Award for Best Telugu Actress and the Nandi Award for Best Actress. She won the Filmfare Award for Best Tamil Actress for her performance in Raja Rani (2013) and Naanum Rowdy dhan (2015). Kochi Times named her in its “List of 15 Most Desirable Women in 2014”. In 2017, she was awarded the Filmfare Award for Best Malayalam Actress for her performance in Puthiya Niyamam (2016), marking her first Filmfare award in Malayalam