Radhika Apte first appeared with a small role in the Hindi film Vaah! Life Ho Toh Aisi! in 2005. In 2009, Apte had her first Indian release, KBC productions' Gho Mala Asla Hava by Sumitra Bhave and Sunil Sukthankar in which she appeared as Savitri, a village girl. 

In 2011, Apte appeared in the anthology film I Am and in Shor in the City under Ekta Kapoor's Balaji Motion Pictures.  For her performance in the latter she was nominated for SIIMA Award for Best Actress in a Supporting Role.

In 2013, she was seen in the Bengali film Rupkatha Noy.About her character she said, "I play Sananda, an IT engineer, who is a single mother of a three-year-old child. Sananda had a dreadful past, which keeps haunting her". Apte's first four 2014 releases were Postcard, Pendulum, Legend and Vetri Selvan in four different languages - Bengali, Telugu and Tamil, respectively—after which another film of hers, Lai Bhaari, released. Pendulum, which was described by Apte as a "story on magic realism which takes you through multiple layers of parallel realities, or apparent realities", had her playing a working woman in relationship with a younger man, while in Vetri Selvan she had played the role of a lawyer. 

In 2015, Apte gained wider recognition for her roles in six feature films released in the first eight months. In the year's first release, Sriram Raghavan's Badlapur, she had a minor supporting role, for which she shot for six days.

In 2018, Apte co-starred with Akshay Kumar and Sonam Kapoor in R. Balki's comedy-drama Pad Man, based on a short story in Twinkle Khanna's book The Legend of Lakshmi Prasad. It is inspired by the life of Arunachalam Muruganantham from Tamil Nadu, who campaigned for menstrual hygiene in rural India. Apte's role was that of a shy homemaker whose husband (Kumar) invents low-cost sanitary napkins. Saibal Chatterjee of NDTV wrote, "Radhika Apte is, as always, a scene-stealer. She contributes majorly to ensuring that the exchanges between the protagonist and his wife do not veer into corniness."

Among Apte's upcoming films are three Hindi language projects, The Field, the feature debut of Rohit Karn Batra, Leena Yadav's Parched, a U.S.-Indian co-production, and Bombairiya, an Indo - British production and a Tamil projects Ula.