Genelia did her first modeling assignment at the age of 15. She was selected for the Parker Pen commercial with Amitabh Bachchan, just two days before her exams, and had to shoot the next day. Initially, she refused, because of her exam the next day, but the director persuaded D'Souza to shoot for the commercial. She gained recognition with the ad and was also complimented by Bachchan

When Genelia was offered a role in 'Tujhe Meri Kasam', initially she turned it down, as she was not keen to pursue a career in acting. The team kept contacting her for two months and she was convinced only after watching the Telugu version. Her first was also opposite Riteish Deshmukh, who is now her husband

Tamil director, S. Shankar, was impressed with her performance in the Parker Pen commercial and decided to cast her in a leading role in his 2003 Tamil film 'Boys'. D'Souza was selected among 300 girls, who had auditioned for the movie. She made her Tamil debut with this film opposite Siddharth

In the same year, Genelia made her Telugu debut with the film Satyam opposite Sumanth. The film opened to positive reviews. With this, Genelia had three releases in 2003, all marking her debut in different languages

Genelia's second Hindi film was 'Masti' which was released in 2004. She was once again paired opposite Riteish in the film

Much before Jr NTR became a pan India sensation, Genelia starred opposite him in the film 'Samba' which was released in 2004. The film was a moderate success at the box office. It was remade in Kannada as Mandya. It was dubbed in Hindi as the same name

Genelia was cast opposite Nithin in this Telugu sports action film directed by the ace SS Rajamouli with a script written by RRR writer Vijayendra Prasad

In 2005, Genelia did her first film with Vijay, titled 'Sachein' in Tamil. The film released on 14 April 2005 with positive reviews and was a commercial success, eventually gaining a cult following in the subsequent years

In June 2008, following a nearly 5–year hiatus in Hindi cinema, she appeared in 'Mere Baap Pehle Aap', opposite Akshaye Khanna which failed to make profit at the box–office

In the same year, she featured in the biggest hit of her career. After the release of 'Jaane Tu...Ya Jaane Na', Genelia came to be known by her character name 'Aditi' aka 'Meow'

The coming-of-age romantic drama about college friends hit a chord with the audience making it an instant classic

In 2010, D'Souza appeared in Chance Pe Dance and Orange, both receiving poor reviews from critics. Chance Pe Dance marked her first with Shahid Kapoor as well

In 2010, Genelia featured alongside Dhanush in the Tamil film 'Uthamaputhiran' which was a moderate success

In 2011, Genelia was seen in her first and only Malayalam film 'Urumi' starring Prithviraj Sukumaran in the lead. She played the role of a Muslim warrior princess Arackal Ayesha in the film

In 2011, she gave a stellar performance as Maya in the action thriller 'Force' starring John Abraham

In 2012, just before their marriage, Genelia and Riteish got together for a romantic comedy titled 'Tere Naal Love Hogaya'

Genelia limited her screen appearances after her marriage and starting a family. She made a special appearance in Riteish's Marathi film 'Lai Bhaari' through a song. This was her first Marathi film appearance

In 2022, Genelia marked her return to full-time acting with 'Mister Mummy' opposite her husband. Directed by Shaad Ali, the movie involved a man getting pregnant

In the same year, Genelia made her full-length feature Marathi debut with Riteish Deshmukh's directorial 'Ved'. The movie is a remake of the Telugu film 'Majili'. With a gross collection of Rs 75 crore (US$9.4 million), it became the highest-grossing Marathi film of 2022 and the fourth highest-grossing Marathi film of all time, surpassing Deshmukh's own Lai Bhaari (2014)

In 2023, Genelia was seen in the film 'Trial Period' playing a single Bengali mother who hires a father for her son