She received critical acclaim and box office success for film Aankhen. So far, her biggest hit has been the 2004 movie Main Hoon Na, in which she starred as Shahrukh Khan's love interest. The film grossed a total of Rs 330,000,000 and was the second best selling movie of that year. Later, Sushmita played a lawyer in Main Aisa Hi Hoon opposite Ajay Devgan. In 2005, she also starred in a remake of Cactus Flower, called Maine Pyaar Kyun Kiya?: Sen played the lead opposite Salman Khan and Katrina Kaif. Her most recent movies include Karma, Confessions and Holi (2006) opposite Naomi Campbell, Do Knot Disturb, Ram Gopal Varma Ki Aag (2007) and Dulha Mil Gaya (2010).
Sushmita has signed three big projects, one of which has been reported that she will portray the slain Pakistan Peoples Party leader Benazir Bhutto in a film co-produced by Zaid Aziz and Henna Rai of the Karachi production company Vox Vision, and Leicester-based Sum Films. Tentatively titled Benazir Bhutto: The Movie, the film will be shot in locations in Pakistan, the US, Britain and Dubai, where Bhutto spent years as a student and later as a political leader in exile. When Sushmita was asked about this big opportunity, she excitedly said, “Yes, I am keen to play the role.”. The second being Farah Khan's untitled venture opposite Salman Khan, and the third one being veteran actress Rekhha's biopic titled Sitare under the banner of Red Chillies Entertainment.
Recently she starred in Do Knot Disturb with long-time screen partner Govinda. The film failed to do well.