Acclaimed actor (2016–present)
Tripathi's first film as a lead actor was the neo-noir thriller Gurgaon (2017), which earned critical acclaim but emerged as a commercial disaster at the Box office. The same year, he also appeared in pivotal roles in several critical and commercially successful films such as the romantic comedy-drama Bareilly Ki Barfi and the comedy Fukrey Returns. He followed it up with the black comedy-drama Newton alongside Rajkummar Rao, which earned him his first nomination for the Filmfare Award for Best Supporting Actor. Newton was also India's official entry for the Academy Award for Best International Feature Film at the 90th Academy Awards.
In 2018, he starred alongside Rao and Shraddha Kapoor in the horror comedy Stree, which earned him high critical acclaim and the Screen Award for Best Supporting Actor, in addition to his second nomination for the Filmfare Award for Best Supporting Actor. Later that year, he made his debut in Tamil cinema with the Rajinikanth-starrer action drama Kaala. The same year, he also starred as Akhandanand Tripathi a.k.a. "Kaleen Bhaiya", a mafia don in the Amazon Prime crime drama thriller web series Mirzapur (2018–present) which earned him widespread critical acclaim and recognition, and a nomination for the Filmfare OTT Award for Best Supporting Actor in a Drama Series for the second season.
In 2019, Tripathi starred in several critically acclaimed supporting roles in commercial successes such as the romantic comedy-drama Luka Chuppi, the drama thriller The Tashkent Files and the biographical drama Super 30. The same year, he starred as Khanna Guruji, a spiritual leader alongside Saif Ali Khan, Nawazuddin Siddiqui, Kalki Koechlin and Ranvir Shorey in the second season of the neo-noir crime thriller Sacred Games (2018–19), which earned him high critical acclaim and a second nomination for the Filmfare OTT Award for Best Supporting Actor in a Drama Series. He also starred in the Disney+ Hotstar legal drama web series Criminal Justice as a lawyer, and reprised his role in the second (Behind Closed Doors (2020)) and third season (Adhura Sach (2022)). The second season earned him a nomination for the Filmfare OTT Award for Best Actor In A Drama Series.
In 2020, Tripathi starred alongside Chris Hemsworth, Randeep Hooda and David Harbour in his first Hollywood film, the Netflix action thriller Extraction. The same year, he received dual nominations for the Filmfare Award for Best Supporting Actor for his performances in the biographical drama Gunjan Saxena: The Kargil Girl and the black comedy Ludo. His performance in the latter won the IIFA Award for Best Supporting Actor.
In 2021, for a second consecutive year, Tripathi received dual nominations for the Filmfare Award for Best Supporting Actor for his widely acclaimed performances in the social comedy-drama Mimi and the biographical sports drama 83, winning the award for Mimi. His performance in Mimi also earned him the National Film Award for Best Supporting Actor. The same year, he also starred in the ZEE5 biographical comedy Kaagaz (2021), which earned him a nomination for the Filmfare OTT Award for Best Actor in A Web Original Film.
In 2023, he starred in the satirical comedy-drama OMG 2 alongside Akshay Kumar and Yami Gautam and the comedy Fukrey 3.
He next portrayed the former Indian Prime Minister Atal Bihari Vajpayee in the biographical drama Main Atal Hoon. The film was theatrically released in India on 19 January 2024.
Tripathi was the brand ambassador of Bharat Rang Mahotsav (National Theatre Festival) for the year 2024.
In 2024, he reprised his role as Rudra in Stree 2.
His first release of the year 2025 was the sequel Metro... In Dino.