Samantha made her acting debut in the Telugu film 'Ye Maaya Chesave', directed by Gautham Vasudev Menon. She starred opposite Naga Chaitanya, marking the beginning of their professional and personal relationship. She won the Filmfare Award for Best Debut Actress – South for her performance.

Following her debut, Samantha starred in several successful Telugu films, including 'Brindaavanam' opposite Jr. NTR and 'Dookudu' opposite Mahesh Babu. These films established her as a leading actress in Tollywood.

Samantha's performance in S.S. Rajamouli's fantasy film 'Eega' (titled 'Naan Ee' in Tamil) garnered her critical acclaim. This film further cemented her position in the industry and showcased her versatility as an actress. She received a Filmfare Award for Best Telugu Actress for her role.

Samantha continued to star in successful Telugu films like 'Seethamma Vakitlo Sirimalle Chettu', alongside Venkatesh and Mahesh Babu, solidifying her star power and popularity among the Telugu audience.