Sethupathi accompanied a group of actors who went to director Selvaraghavan's studio to audition for his gangster film Pudhupettai (2006) and was selected to play Dhanush's friend in the film. Following Pudhupettai, he was associated with a Tamil-Kannada bilingual film called Akhaada. While he was selected to play the lead in the Tamil version, the director offered him the antagonistic role in its Kannada version. However, the film did not see a theatrical release. After making an appearance in Prabu Solomon's Lee (2007), he was cast by director Suseenthiran in minor supporting roles in his first two projects, Vennila Kabadi Kuzhu (2009) and Naan Mahaan Alla (2010). Sethupathi would later credit Suseenthiran with having had an "important role in helping him realise his dreams". Suseenthiran, furthermore, recommended Sethupathi to director Seenu Ramasamy and Sethupathi landed his first lead role in Ramasamy's drama film Thenmerku Paruvakaatru (2011), in which he portrayed a shepherd, the film went on to win three National Film Awards including the prize for the Best Tamil Feature Film of that year.