The movie was well received, and subsequently she started receiving Telugu film offers. She left Tamil cinema for a while to concentrate on the Telugu film industry. She made her Telugu debut in Satyam in 2003 opposite Sumanth, in which she played the role of a medical student, for which she was praised for her performance. The movie was a box-office success,and it raised her profile in the Telugu film industry.
Broader public recognition came to D'Souza in her second Hindi movie, Masti in 2004, which was also opposite Ritesh Deshmukh. The comedy focuses on three close friends who reunite after three years, but are now married and are being harassed by their wives. D'Souza portrayed the character of one of the wives.
Indian film critic Taran Adarsh was complimentary of D'Souza's role, saying, "Amongst the wives, Genelia is the best, Genelia looks the stern and demanding wife and is sure to be noticed." This film was a critical success, and also fared well at the UK box office. The same year, she appeared in the Telugu fim Samba. Her final Telugu movie in 2004 was Sye, set against a rugby union backdrop, in which she played the role of a vivacious college student. In 2005, D'Souza experienced a slump in her career. Her first Telugu movie in 2005, Naa Alludu, was commercially unsuccessful. Later that year, she starred in the Tamil romantic entertainer Sachein, in which she played the role of Shalini, a typical fashionable college-going Tamil girl.
A review in The Hindu noted, "Genelia, who hardly made an impression in Boys, makes much impact in Sachein." The movie evoked mixed response from audiences, but was well received with the younger generation, and was a commercial success. She later appeared in the Telugu patriotic movie Subhash Chandra Bose set against a backdrop of Pre-independence period, which was also an economic failure. The year 2006 marked a significant turning point in D'Souza's career. She completed two Telugu movies in early 2006, one was the romantic comedy Happy, and the other was Raam. She then portrayed the role of Haasini, a vibrant, effervescent and a happy-go-lucky young girl, in the 2006 Telugu romantic film Bommarillu, alongside Siddharth Narayan. The movie, a blockbuster at the box-office, grossed Indian rupee250 million (US$ 5.68 million) in India, and also won the 2006 Golden Nandi award.
Her character was well-received by critics, and garnered her the Telugu Filmfare Award for Best Actress, besides Nandi Special Jury Award and Santosham Award for Best Actress. Following the success of Bommarillu, D'Souza played the role of the daughter of a local don, in the Tamil gangster film Chennai Kadhal. D'Souza's performance received ambivalent reviews. While The Hindu praised her performance, Rediff criticized her commenting, "Genelia stands up yet again to prove the point that if you are pretty and well dressed, you can get away with anything, without acting." Shortly after wards in 2007, D'Souza played the role of sister of a notorious gangster in the blockbuster Telugu movie Dhee. Her performance was appreciated, netting her the FNCC Best Actress Award. The following year, D'Souza appeared in the 2008 Telugu romantic thriller Mr. Medhavi, in which she portrayed the role of a student from Canada. The movie was moderately successful, nonetheless D'Souza was complimented for her performance. ( Telugu-news.com/ )
She made her Kannada debut in Satya In Love the same year, in which she was appreciated for her smile. Later, she was cast in a leading role in Santhosh Subramaniam, a Tamil remake of Bommarillu. The film also turned out to be rather successful as its predecessor. Sify described D'Souza's portrayal as "the soul of the film" and the film's "biggest strength", however Rediff described her character as "appears a little too good to be true."
It has been rightly quoted in James Cameron’s historical movie ‘TITANIC’ that “every woman’s heart is an ocean of secrets.”
When steady relationships go awry, it is mostly due to the involvement of a third person i.e. the 'other woman', Top Bollywood affairs 
