In 1994, as a teenager, Sen participated in the Femina Miss India contest. She won the title ‘Femina Miss India Universe’, earning the right to compete at the Miss Universe 1994 contest.

After her reign as Miss Universe, Sushmita became an actress. Her first film Dastak was in 1996, in which she played the victim of a stalker, played by Sharad Kapoor. Mukul Dev starred as the lead actor. She then starred in the 1997 Tamil action film Ratchagan. Two years later her appearance as Rupali in David Dhawan’s movie Biwi No.1 won her the Filmfare Best Supporting Actress Award in 1999. Biwi No.1 was the second highest-grossing movie of 1999. The same year, she was also nominated for her role in Sirf Tum in the same category. She appeared in a dance song in the movie Fiza, in the year 2000.

Sen adopted a baby girl, Renee, in 2000 and a second girl, Alisah, in 2010. Sen is currently dating Rohman Shawl, who is a fashion model. In an interview, Sen revealed that the she met Shawl through Instagram. The couple has been very active on social media giving the fans a glimpse into their love life.

She received critical acclaim and box office success for the film Aankhen, starring opposite Arjun Rampal. The film co-starred Amitabh Bachchan, Akshay Kumar, Aditya Pancholi and Paresh Rawal. 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. She also played the leading role in Karma Aur Holi.

In 2010, Sushmita played the role of a successful supermodel called Shimmer in Dulha Mil Gaya; the film was a moderate success that year. She additionally appeared in the action-comedy film No Problem the same year. In 2015, she starred in a Bengali drama film titled Nirbaak. In Sushmita’s career, this was her first film in Bengali language.

As a celebration of 65th Miss Universe, 23 years after winning the pageant, she returned to Manila, Philippines, in January 2017, as one of the judges of the Miss Universe 2016 beauty pageant. The pageant took place at the Mall of Asia Arena, Pasay, Metro Manila, Philippines on 30 January 2017. Joining her as judges were Cynthia Bailey, Mickey Boardman, Francine LaFrak, Miss Universe 2011 Leila Lopes, and Miss Universe 1993 Dayanara Torres.