Sheirgill began his film career with the 1996 period thriller Maachis. Though the film was commercially successful, his performance not earned him much fame. His breakthrough came in 2000 with the blockbuster musical romance Mohabbatein, which became the highest-grossing Bollywood film of the year, following which he starred in several other box-office hits including Mere Yaar Ki Shaadi Hai (2002), Munna Bhai M. B. B. S (2003), Hum Tum (2004), A Wednesday! (2008), Tanu Weds Manu (2011), Special 26 (2013), Happy Bhag Jayegi (2016) and De De Pyaar De (2019). His highest-grossing releases came with the comedy-drama Lage Raho Munna Bhai (2006), the drama film My Name Is Khan (2010) and the romantic comedy Tanu Weds Manu: Returns (2015), all of which rank among the highest-grossing Indian films of all time. The latter earned him a nomination for the Filmfare Award for Best Supporting Actor.