Asin  signed films with four leading actors of the Tamil industry: Surya, Vikram, Vijay and Ajith in Ghajini, Majaa, Sivakasi and Varalaru respectively.

The venture which provided the breakthrough for Asin to become the leading South Indian actress was her Tamil film, 'Ghajini'. The film, co-starring Surya and Nayantara and directed by A. R. Murugadoss, helped Asin secure the Tamil Filmfare Award for Best Actress.

Asin had two big releases in 2005, 'Sivakasi' and 'Majaa'. Despite the latter becoming an average grosser, the former also went on to be a successful venture at the box office, despite Asin's poorly etched out role.

In 2006, 'Varalaru' opposite Ajith Kumar, became the biggest blockbuster of 2006 in Tamil cinema, after releasing for Diwali 2006.

Asin then appeared in Pawan Kalyan's Telegu Film 'Annavaram', another successful venture in which she had a poorly-etched out role.

In January 2007, Asin appeared opposite Ajith Kumar and Vijay in two different films, 'Aalwar' and 'Pokkiri', with the latter becoming a super success, whilst Aalwar became a failure.

Her final project of the year was opposite 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 appeared in her first dual role in K. S. Ravikumar's magnum opus 'Dasavathaaram' opposite Kamal Haasan, who portrayed ten roles. The film, which was under production since September 2006, became Asin's largest film till date. Dasavathaaram subsequently went on to become one of the biggest blockbusters in South Indian film history.