Dhupia made her film debut in the 2003 Bollywood film Qayamat: City Under Threat (2003), which performed averagely at the box office. She rose to fame with her role in the film Julie and then appeared in Sheesha (2005) in a dual role of twin sisters, but the film did not do well at the box office. She then starred in films such as Kyaa Kool Hai Hum (2005) and Shootout at Lokhandwala (2007), which did well at the box office, and also featured in a segment of the anthology film Dus Kahaniyaan (2007).
In the following years, Dhupia appeared in supporting roles in multiple critically and commercially acclaimed films including Chup Chup Ke (2006), Ek Chalis Ki Last Local (2007), Mithya (2008), Maharathi (2008), Singh Is King (2008) and Dasvidaniya (2008). In 2011, she plays Eva Braun in the film Dear Friend Hitler -a film about Mahatma Gandhi.
Her most recent films are Paying Guest, Action Replayy and De Dana Dan. She has also worked on her first international project with Chris Kattan in IFC’s Bollywood Hero.