2016–present
In 2016, he was first seen in the police action thriller Sethupathi directed by S. U. Arunkumar. Sethupathi received praise for his performance. Vishal Menon of The Hindu said that it was a good thriller and a better family drama. Latha Srinivasan of DNA wrote that there were no loud over-the-top dialogues and punchlines that were typical of all on-screen cops in Tamil films and Sethupathi outshone many other Kollywood heroes as the cop. 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." 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." He was next seen in the romantic comedy Kadhalum Kadandhu Pogum by Nalan Kumaraswamy. His next release was Iraivi followed by Dharma Durai by Seenu Ramasamy, Aandavan Kattalai and Rekka. He was nicknamed Makkal Selvan (lit. people's man) by Seenu Ramasamy while filming Dharma Durai, and has been popularly known by that since. His next release was the long delayed mystery-thriller Puriyatha Puthir. Then, he appeared in the rural drama Karuppan directed by R. Panneerselvam. 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.
In 2018, his first release was Oru Nalla Naal Paathu Solren directed by Arumugakumar. Then, he acted in the action comedy Junga which was directed by Gokul and was produced by Sethupathi. He then appeared in Mani Ratnam's multi-starrer Chekka Chivantha Vaanam. He then starred in C. Prem Kumar's romantic drama '96 alongside Trisha which released a week after the release of Chekka Chivantha Vaanam. '96 earned him his second Filmfare Award for Best Actor – Tamil. He then acted in the Balaji Tharaneetharan-directorial Seethakaathi, Thiagarajan Kumararaja's Super Deluxe and has acted in a negative role in Karthik Subbaraj's Petta alongside Rajinikanth. During the second half of 2019, he made his Malayalam and Telugu debuts with Maarconi Mathaai and Sye Raa Narasimha Reddy, respectively.
In 2019, Film Companion ranked Sethupathi's performance in Aandavan Kattalai and Super Deluxe among the 100 Greatest Performances of the Decade. His performance in the latter won him the National Film Award for Best Supporting Actor. In 2020, he starred in Ka Pae Ranasingam starring Aishwarya Rajesh. In October 2020, it was announced that Sethupathi would play the lead role of Sri Lankan cricketer Muttiah Muralitharan in the biopic titled 800. Sethupathi later announced that he was opting out of the film on Muralitharan's request after political controversy regarding the role.
In 2021, Sethupathi appeared in Lokesh Kanagaraj's film Master alongside Vijay. He then appeared in the Telugu film Uppena, which was written and directed by Bucchi Babu Sana. After Uppena, Sethupathi appeared in three films in the month of September in 2021, Laabam, Tughlaq Durbar and Annabelle Sethupathi. He appeared in Mughizh in which his daughter makes her debut. Sethupathi also starred in Vetrimaaran's Tamil film Viduthalai Part 1.
As of October 2021 he is the host of MasterChef India – Tamil, which started on 7 August 2021 on Sun TV Network.
In 2022, Vijay Sethupathi appeared in the drama film Kadaisi Vivasayi directed by M. Manikandan. Following, the romantic comedy Vignesh Shivan's Kaathuvaakula Rendu Kaadhal with Nayanthara and Samantha. After Master, Sethupathi again got a villain role in Lokesh Kanagaraj directorial Vikram starring Kamal Haasan in the lead role. Sethupathi played a drug dealer. Vikram broke several box office records and officially became one of the highest-grossing films in Tamil Nadu. Vijay Sethupathi and his mentor Seenu Ramasamy worked together for the fourth time on the family emotion-packed Maamanithan. Sethupathi acted in Malayalam movie 19(1)(a) starring with Nithya Menen and was released by streaming platform Disney+ Hotstar. In December, his action comedy DSP was released to negative reviews. In 2023, Sethupathi appeared in Jawan starring Shah Rukh Khan and Nayanthara in the lead role. Sethupathi played as an arms dealer, which was significantly praised by critics and the audience. Sethupathi joined hands with director Kishor Pandurang Belekar for a silent film titled Gandhi Talks. The next, was the Hindi and Tamil bilingual film, Merry Christmas (2024) directed by Sriram Raghavan. Starring the charismatic duo of Katrina Kaif and Sethupathi, the film failed to charm audiences at the box office despite its star power and critical acclaim. Then, Vijay Sethupathi has hit a majestic milestone with his fiftieth film Maharaja (2024). The film, featuring a gripping narrative about a barber's quest, was a critical and commercial success internationally, especially in China. Sethupathi described it as a comeback after challenging years, underscoring its personal significance. Followed by the film, Viduthalai Part 2 (2024), with the Part 1, was screened at the International Film Festival Rotterdam. In 2025, his two comedy films Ace and Thalaivan Thalaivii were released.