He made his Bollywood debut with Shyam Benegal's National Award winning film Netaji Subhas Chandra Bose: The Forgotten Hero (2004).

His subsequent collaborations with Ghosh for films which include Shob Charitro Kalponik and Noukadubi brought him a higher degree of critical and commercial success.

His biggest commercial success came with the action drama film Zulfiqar (2016),[2] as he continued to draw praise for his performances in Sesh Bole Kichu Nei (2014), Jaatishwar (2014), Kelor Kirti (2016), Posto (2017), Ek Je Chhilo Raja (2018) and Mahalaya (2019).

[8] After his part ended in the series, he made his silver screen debut through Priyojon, directed by Dinen Sengupta, which was a critical and commercial failure.

He made his debut in Bangla cinema through Moner Majhe Tumi, appearing as a parallel lead, which was the highest-grossing film of Bangladesh in 2003.

[13][14] He also made his debut in Bollywood through Shyam Benegal's biographical war film Netaji Subhas Chandra Bose: The Forgotten Hero.

Under Ghosh's tutelage, he gave some of his critically acclaimed performances in films, including The Last Lear, Shob Choritro Kalponik (2008), Chitrangada, and a betrayed husband in Abohoman.

The Times of India stated that "Jisshu Sengupta, in the role of a junkie, has delivered one of the finest performances of his career."

[15][16] Sengupta made a comeback to Hindi cinema through a cameo appearance in Anurag Basu's directorial Barfi!.

[17] Sengupta collaborated with Srijit Mukherji for the latter's musical drama film Jaatishwar co-starring Prosenjit Chatterjee and Swastika Mukherjee.

[23] Sengupta is associated with television from the beginning of his career, since he forayed into showbiz with a mythological series based on Chaitanya Mahaprabhu.

After almost a decade, he made a comeback to television in the fiction category through his own production, titled Aparajito, which aired on Star Jalsha.

Over 8,000 participants including elite runners, beginners, fitness enthusiasts, corporate teams and spirited youngsters took part in the ₹10 lakh prize money event held on 8 February 2014.