[7][8] Sethupathi established himself as a successful actor with films such as Soodhu Kavvum (2013), Idharkuthane Aasaipattai Balakumara (2013), Pannaiyarum Padminiyum (2014), Kadhalum Kadandhu Pogum (2016), Iraivi (2016), Vikram Vedha (2017), '96 (2018), Chekka Chivantha Vaanam (2018), Petta (2019), Master (2021), Vikram (2022), Viduthalai Part 1 (2023), Viduthalai Part 2 (2024), Jawan (2023) and Maharaja (2024).

[9] For playing a trans woman in Super Deluxe (2019), he won the National Film Award for Best Actor in a Supporting Role.

[12] 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.

[10] He graduated with a Bachelor of Commerce degree from the Dhanraj Baid Jain College (an affiliate of the University of Madras) in Thoraipakam.

[10] 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.

[13][14] After a brief stint in the interior decoration business with friends, he joined a marketing company that dealt with readymade kitchens when he saw Koothu-P-Pattarai's poster.

[10] He recalled director Balu Mahendra remarking that he had a "very photogenic face",[13] and motivated him to pursue an acting career; however he never cast Sethupathi in his films.

[14] After making an appearance in Prabu Solomon's Lee (2007),[20] he was cast by director Suseenthiran in minor supporting roles in his first two projects, Vennila Kabadi Kuzhu (2009) and Naan Mahaan Alla (2010).

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.

[33][34] 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.

With regard to Naduvula Konjam Pakkatha Kaanom, The Times of India reviewer M. Suganth cited that Sethupathi "continues his superb show from Pizza conveying Prem's peculiar condition with vacant stares and amusing pauses between his lines", further noting: "That he never makes the character's repetitive dialogues irritating is a proof of his terrific timing".

Malini Mannath from The New Indian Express in her review wrote: "It's laudable that the actor doesn't hesitate to take a role that has him playing a 40-year-old man, greying and with a paunch".

"[45] Rediff reviewer S.Saraswathi cited that "His greatest strength lies in being able to counter the stereotypical image of heroes in commercial cinema today.

The depth in his innocence and the foolhardiness in his love are a couple of things that stand tall in the character he plays, and Vijay Sethupathi has pulled it off in grand style.".

[48] Pannaiyarum Padminiyum, based on its same-titled short film, revolved around an old man and his vintage car Premier Padmini, with Sethupathi starring as its chauffeur.

[53] Behindwoods stated that the stand out element in the film is Vijay Sethupathi, who has managed to attach his performance to the nativity of the location to the best of his ability.

The Times of India reviewer M. Suganth cited that "Vijay Sethupathi redeems everything with a sensitive performance.Balusamy might be the film's central character, but it is Yamalingam who is its beating heart.

"[55] Rediff reviewer S.Saraswathi cited that "Vijay Sethupathi, as a tormented soul loath to pull the lever that will release the trapdoor and take a life, is perhaps the best.

"[56] In July 2015, his first movie as producer Orange Mittai directed by Biju Viswanath got released and met with positive reviews by the critics and entertainment portals.

[59] Malini Mannath of The New Indian Express wrote that, "It is another feather in the cap for Vijay Sethupathi, who is revealing his versatility yet again as he handles his role with remarkable understanding.

"[60] Anupama Subramaniam of Deccan Chronicle wrote that, "Sethupathi's moves are full of energy and enthusiasm and his impeccable dialogue delivery is a treat to watch.

In 2017, he appeared in the neo-noir action thriller film Vikram Vedha in the lead role alongside Madhavan, which earned him his first Filmfare Award for Best Actor – Tamil.

[81] In October 2020, it was announced that Sethupathi would play the lead role of Sri Lankan cricketer Muttiah Muralitharan in the biopic titled 800.

[91] Vijay Sethupathi and his mentor Seenu Ramasamy have combined for the fourth time to deliver the family emotion packed Maamanithan.

[96][97] Sethupathi met Chief minister of Tamil Nadu M.K Stalin on 15 June 2021 and donated ₹25 lakhs as part of the Corona relief fund.

The controversy surrounding Vijay Sethupathi's role in a biopic about Muttiah Muralitharan stemmed from the cricketer's support for the Sri Lankan Government and his political statements.