Naseeruddin Shah started his film career with Shyam Benegal's Nishant (1975). Some of his best portrayals in his early career were in films such as Manthan (1976), Bhumika (1977), Aakrosh (1980), Kundan Shah's Jaane Bhi Do Yaaron (1983), Shekar Kapur's first directorial venture Masoom (1983) and Mirch Masala (1985). He also played his part in mainstream Bollywood - in such films as Umrao Jaan, Subhash Ghai's Karma (1986). He teamed up with his wife Ratna Pathak, in The Perfect Murder (1988) and was one of the three heroes in Rajiv Rai's Tridev (1989), which was a huge hit. He played a Kenyan police officer in Rajiv Rai's Vishwatma (1992) and played roles in Kabhie Haan Kabhie Naa (1993) and Mohra (1994). He is also an equally successful name in theatre and television.

He was seen on television in Gulzar's show on Mirza Ghalib, which was aired on Doordarshan. In 1989, he acted as the Maratha King Shivaji, in another television series Bharat Ek Khoj, based on Jawaharlal Nehru's book The Discovery of India, directed by noted film director Shyam Benegal. He also appeared in many international films most notably playing Captain Nemo in the Hollywood production, The League of Extraordinary Gentlemen. He started a theater group called Motley Productions with Tom Alter and Benjamin Gilani. He was the narrator for the movie Paheli and the Karadi Tales audiobook series. In 1998, he played the role of Mahatma Gandhi in the play Mahatma Vs. Gandhi, (which looked at the Mahatma's relation with Harilal Gandhi, his first son). With this, he achieved his objective of portraying Mahatma Gandhi;  he had audioned to play the role in Richard Attenborough's Gandhi.

Incidentally, in 2000, he again portrayed the Mahatma, this time on film, in Hey Ram. His performance in Sarfarosh (1999) was widely acclaimed. He played the villain with the dual identity of a Ghazal singer and Pakistani spy who supports terrorism in India. In 2004, he worked in the Indian adaptation of Shakespeare's Macbeth, titled Maqbool. He made his Pakistani film debut in the critically-acclaimed and controversial film Khuda Ke Liye by Shoaib Mansoor where he played a short, yet powerful cameo. He came in for acclaim in his role in the Iqbal (2005), a role which won him a National Film Award for Best Supporting Actor. He was seen in Rahul Dholakia's Parzania, a movie based on the Godhra riots. He again achieved critical success for his role in A Wednesday (2008) and in the same year, he was seen in Jaane Tu Ya Jaane Na.

He has directed plays written by Ismat Chughtai and Saadat Hasan Manto. He made his directorial debut in the movie, Yun Hota To Kya Hota, which was released in 2006. The movie was a multi-starrer with actors such as Paresh Rawal, Irfan Khan and newcomer Ayesha Takia and his own son Imaad Shah. He has won three National Film Awards, a Padma Shri and a Padma Bhushan. The actors upcoming films include Sunglass, Shoonya, Exchange Offer, Nidar - The Fearless, Ishqiya, Red Alert - The War Within, The Falling, Allah Ke Banday, and 7 to the Palace. Most of these films are slated for a 2009 release.