With regard to Naduvula Konjam Pakkatha Kaanom, The Times of India reviewer M. Michael’s nightmarish experience, and his fear and horror when he’s trapped in the mansion, is perfectly conveyed by the actor". His voice perfectly modulated, he proves his versatility and acumen to handle any role. Malini Mannath from The New Indian Express in her review of Pizza wrote: "Sethupathy, a delight to watch, carries the entire film on his shoulders. He enacted the role of Michael, a delivery boy in the former and a young man named Prem who sustains short-term memory loss two days before his marriage in the latter, with his performance in both films being praised by critics. Sasikumar in the lead role, and then played the lead roles in the directorial debuts of Karthik Subbaraj and Balaji Tharaneetharan, the thriller film Pizza and the comedy entertainer Naduvula Konjam Pakkatha Kaanom, respectively. He was first seen in a negative role in Sundarapandian which featured M. 2012–2013 Ģ012 marked a turning point in Sethupathi's career all his three releases were critical and commercial successes, resulting in a rise in his popularity. Director Seenu Ramasamy identified Sethupathi's talent during the audition of his film 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. Sethupathi would later credit Suseenthiran with having had an "important role in helping him realise his dreams". 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). However, the film did not see a theatrical release. While he was selected to play the lead in the Tamil version, the director offered him the antagonistic role in its Kannada version. Following Pudhupettai, he was associated with a Tamil-Kannada bilingual film called Akhaada. 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. He worked with Karthik Subbaraj on many short films, who later cast him in his first feature film, subsequently yield him the Best Actor award for one of his films at the Norway Tamil Film Festival short film competition.
He also acted in television series, including the well-known series Penn that began in March 2006, as well as several short films as part of the television show Nalaya Iyakunar for Kalaignar TV. He made his beginnings as a background actor, particularly playing the role of the lead character's friend in a few films.
He subsequently joined the Chennai-based theatre group Koothu-P-Pattarai as an accountant and actor where he observed actors from close quarters. He recalled director Balu Mahendra remarking that he had a "very photogenic face", and motivated him to pursue an acting career.
After a brief stint in the interior decoration business with friends, he joined a marketing company that dealt with readymade kitchens when he saw Koothupattarai’s poster. Unhappy with his job, he returned to India in 2003. The two dated, eventually marrying in 2003. While in Dubai, he met his future-wife, Jessie, online. He had to take care of three siblings and moved to Dubai, United Arab Emirates as an accountant because it paid him four times more than what he was making in India. A week after he finished college, he joined as an account assistant at a wholesale cement business. He graduated with a Bachelor of Commerce degree from the Dhanraj Baid Jain College (an affiliate of the University of Madras) in Thoraipakam. Sethupathi did a series of odd jobs for pocket money: salesman at a retail store, cashier at a fast food joint and a phone booth operator. At age 16, he auditioned for a role in Nammavar (1994), but was rejected due to his short height. According to Sethupathi, he was a "below-average student right from school" and was neither interested in sports nor extra-curricular activities.
He attended the MGR Higher Secondary School in Kodambakkam and Little Angels Mat. He lived in Ennore located in North Chennai. Vijay Sethupathi was born and raised in Rajapalayam until he moved to Chennai in class six.