After completing his graduation he went to Dubai for job but was not happy with his job and so he returned to India in 2003. He recalls that a photographer stated that he had a "very photogenic face", and persuade him to pursue an acting career. Sethupathi was one of the actors among several others who went to director Selvaraghavan's to audition for his gangster film Pudhupettai in 2006 and it was he who was picked to play Dhanush's friend in the film.
After doing lots of side roles he finally appeared in his first lead role in Ramasamy's film Thenmerku Paruvakaatru in 2011. The following year, marked as a decisive point in Sethupathi's career; all his three releases in 2012 were commercial & critical successes, which resulted in a rise in his fan following. His first film released in 2012 was Sundarapandian in which he featured as the lead villian and then portrayed the lead roles in the directorial debuts of Balaji Tharaneetharan and Karthik Subbaraj, the comedy film Naduvula Konjam Pakkatha Kaanom and the thriller film Pizza, respectively.
He married his girlfriend Jessie in 2003 with whom he has a son Surya and a daughter Shreeja.