Her passion for acting and modeling has made her successful in her films. She made her acting debut in the 2003 Telugu film Seenu Vasanthi Lakshmi, a remake of the Tamil film Kasi, which itself was a remake of the Malayalam film Vasanthiyum Lakshmiyum Pinne Njaanum. She essayed the role of a sexually exploited poor sister of a blind man in the film. This made possible her entry into the Malayalam film industry in the same year, starring in the film Kaazcha alongside superstar Mammootty. For her portrayal of a mother of three children, who struggles to accommodate another child, a victim of the Gujarat earthquake, she received rave reviews and the Asianet Award for Best Female New Face of the Year. She then started acting in malayalam movies, where she acted with all the superstars such as Mammootty, Mohanlal, Suresh Gopi and Jayaram.
In 2005, she acted in her first Tamil-language film, Thavamai Thavamirundhu, a drama that dealt with familial bond, depicting a father-son relationship, in which she was paired opposite actor-director Cheran. She played a simple college girl in the film, which garnered highly postive reviews and won several awards at major Indian award ceremonies, including a National Film Award (for Best Film on Family Welfare). Padmapriya herself was awarded the Filmfare Award for Best Debut Actress for her critically acclaimed performance. She next starred in the Malayalam film Rajamanikyam again alongside Mammootty. The comedy film, featuring also Rahman and Sindhu Menon, was an universal blockbuster, becoming the most popular film of the year, Padmapriya's highest-grossing film till date and even the highest-grosser of Mammootty and in the history of Malayalam cinema itself, after Twenty:20.
In 2006, she appeared in 6 films. Her first release that year was Vadakkum Nathan, following which she starred in the Tamil film Pattiyal, in which she portrayed a salesgirl at a garment company. The Vishnuvardhan-directed gangster film, in which she shared screen space with Arya, Bharath and Pooja Umashankar, was a commercial and critical success, becoming one of the highest-grossing Tamil films of the year. Later that year, she acted in the Malayalam-language film Karutha Pakshikal and Yes Your Honour, which both were well appreciated by critics. Padmapriya's performance in both the films received positive reviews, particularly her portrayal as Poongodi, a street beggar, in the former fetched her rave accloades and earned her several awards including a Filmfare Best Actress Award.
2007 she had even 7 releases, the first being Anchil Oraal Arjunan. Next she starred in Veeralipattu and Satham Podathey in Tamil film. The latter was a psychological thriller directed by Vasanth, where she enacted the role of a helpless wife, who gets kidnapped by her former husband, whom she had divorced due to his alcohol addiction. Following Satham Podathey, she appeared in the films Naalu Pennungal in Malayalam, directed by Adoor Gopalakrishnan and Mirugam in Tamil, directed by Samy. In Naalu Pennungal, which fetched its director the National Film Award for Best Directing, she essayed the role of a street prostitute, whilst in Mirugam, she played a tomboyish wife to a ruffian, who behaves like an animal, for which she won the Tamil Nadu State Film Special Award for Best Actress.
Currently she is working on half-a-dozen films, which include her Hindi debut venture Striker opposite Siddharth Narayan,her Kannada debut film Thamassu alongside Shivrajkumar,a cowboy-based film Irumbu Kottai Murattu Singam in Tamil,Kutty Shranku with Mammootty once again in Malayalam and ace director Vishwanath's comeback film Sumadhuram in TeluguWhilst she will be enacting the role of a bar owner in Striker, she will appear as a human rights activist in Thamassu and as an army officer’s daughter in Irumbu Kottai Murattu Singam.