Nayanthara made her acting debut in the 2003 Malayalam film Manassinakkare with Jayaram and Vismayathumbathu with super star Mohanlal (2004). She also acted in a supporting role in the super hit Malayalam film Natturajavu before foraying into Tamil and Telugu cinema. She made her debut in Tamil cinema with Ayya (2005) and Telugu with Lakshmi (2006). Both were successful. After this she was the female lead in 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), making her the highest paid actress in South Indian cinema.
