In 2000, he directed and wrote dialogues of the action thriller Pukar which earned him the Nargis Dutt Award for Best Feature Film on National Integration.

He followed it by directing two moderate commercial successes—the biopic The Legend of Bhagat Singh (2002) and the action thriller Khakee (2004) —both of which earned him nominations for the Filmfare Award for Best Director.

His highest-grossing film came in 2009 with the romantic comedy Ajab Prem Ki Ghazab Kahani starring Ranbir Kapoor and Katrina Kaif, which grossed ₹1.2 billion (US$14 million) worldwide.

[1] Santoshi started his career in 1982 as an assistant director on Govind Nihalani on the coming-of-age film Vijeta (1982) and the crime drama Ardh Satya (1983).

Santoshi made his directorial debut with the action drama Ghayal (1990), starring Sunny Deol and Meenakshi Seshadri in lead roles.

It opened to universal critical acclaim, with widespread praise for its storyline, execution and themes; moreover, It also emerged as a major commercial success at the box-office, ranking as the fifth highest-grossing Hindi film of the year.

Santoshi began the new millennium with writing and directing the action thriller Pukar (2000) starring Anil Kapoor and Madhuri Dixit in lead roles.

The film tells the story of a notorious terrorist who manipulates an Indian army major's jilted lover into helping him obtain a classified military code.

[11] The film starred an ensemble cast of Rekha, Manisha Koirala, Dixit, Mahima Chaudhary, Anil Kapoor, Ajay Devgn and Jackie Shroff in lead roles.

[18] Santoshi wrote and directed the ensemble neo-noir crime thriller Khakee (2004), starring Amitabh Bachchan, Akshay Kumar, Devgn, Aishwarya Rai and Tusshar Kapoor in lead roles.

[21][22] He next wrote and directed the social action drama Halla Bol (2008) starring Devgn, Vidya Balan and Pankaj Kapur in lead roles.

The film was based on the life of activist Safdar Hashmi, who was killed by political rivals while performing in a street play (by the name of Halla Bol) in 1989.

[25] Santoshi's career prospects improved when he wrote and directed the romantic comedy Ajab Prem Ki Ghazab Kahani (2009) starring Ranbir Kapoor and Katrina Kaif in lead roles.

[26][27] After a 4-year hiatus, Santoshi made a comeback with the action comedy Phata Poster Nikhla Hero (2013) starring Shahid Kapoor and Ileana D'Cruz in lead roles.

[28][29][30] After a 10-year hiatus, Santoshi made a comeback with three diverse ventures – the historical Gandhi Godse – Ek Yudh, the social comedy-drama Aalay Mazya Rashila and the romantic comedy Bad Boy.