Shah became active in mainstream Bollywood cinema with the 1980 film Hum Paanch. In 1982, he acted in the film Dil Aakhir Dil Hai directed by Ismail Shroff, opposite Rakhee. One of his most important films, Masoom, was released in 1983 and was shot at St Joseph's College, Nainital. His next major success in mainstream films was the 1986 multi-star film Karma where he acted alongside veteran Dilip Kumar. Starring roles for films such as Ijaazat (1987), Jalwa (1988) and Hero Hiralal (1989) followed. In 1988 he played opposite his wife Ratna Pathak as Inspector Ghote, the fictional detective of H. R. F. Keating's novels in the Merchant Ivory English language film The Perfect Murder. He acted with Aditya Pancholi in films like Maalamaal (1988) and Game (1993).
In the 1970s, Shah met and fell in love with Ratna Pathak, the daughter of Dina Pathak, a well-respected character actress. Ratna's sister, the actress Supriya Pathak, is married to the actor Pankaj Kapoor, who is the father of Shahid Kapoor by his first marriage. During the 70s and 80s, Naseeruddin Shah and Ratna Pathak co-starred in several films including Mirch Masala and The Perfect Murder. They were in a live-in relationship for many years, while Shah put together the mehr required to divorce Manara. Shah and Pathak were finally married in 1982. By his second marriage, Shah has two sons, Imaad and Vivaan, both of whom are aspiring actors. The couple lives in Mumbai with Heeba, Imaad and Vivaan.