Genelia made her debut in Bollywood in 2003. Her first Hindi film was Tujhe Meri Kasam opposite Ritesh Deshmukh. She left Bollywood for a while to concentrate on the Tollywood Telugu industry.

She first hit the lime-light with a Parker Pen commercial with Amitabh Bachchan and further did a Fair and Lovely ad with Krishnamachari Srikkanth. The ace Tamil director, Shankar was very much impressed with her performance in both the ads and cast her in a leading role in his Tamil version of "Boys" in 2003. The film was a box-office hit and launched her career in south India.

She acted in some successful Telugu films including Satyam, Happy, Samba and Sye. She followed it up with a pairing with actor Venkatesh in Subhash Chandra Bose.

She returned to the Tamil industry with Sachein with Vijay. It was average at the box office. Her second Hindi movie was Masti and was also opposite Ritesh. This film was a moderate success. She played the role of Haasini in Bommarillu, which also starred Siddharth Narayan in the lead. This movie was a major commercial and critical success and she won the Filmfare Award as the Best Actress for her performance, besides other awards. She was also a part of Mani Ratnam's stage show,Netru, Indru, Naalai. She came back into Kollywood with Santhosh Subramaniam, which is the remake of Bommarillu. The film also turned out to be a rather successful as its predecessor. Her debut film in Kannada Satya In Love grossed 4 crores in its opening week thus setting a new record in the Kannada film industry.

She once again appeared in Bollywood in Mere Baap Pehle Aap alongside Akshaye Khanna, which was moderately successful. Her final breakthrough in Bollywood was through the blockbuster, Jaane Tu Ya Jaane Na, where she is the heroine in the role of Aditi Mahant aka "Meow". Her role has been widely admired for her sweetness and freshness, and new style of acting. The movie has debutant Imran Khan, Aamir Khan's nephew, as the hero. The movie released in July 4, 2008 and was a success across India and overseas.^[5] Her career in South India also continues with her latest Telugu Film Ready becoming a major box office hit. Her next film It's My Life, which is again a remake of Bomarillu with Harman Baweja is to be released in 2009. She will also act in David Dhawan's next film which is called Hook Ya Crook opposite John Abraham & Uday Chopra for the first time which is a cricket film, the film will be released in 2009. She also has the other film on her hand which is to released by mid of 2009 which is titled Life Partner with Tusshar Kapoor