Samantha made her acting debut with GVM's Ye Maaya Chesave (2010), also starring Akkineni Naga Chaitanya. The film fetched her a Nandi Award and Filmfare Award for Best Debut Actress.
Samantha married the co-star of her first film, Naga Chaitanya, in a glitzy ceremony on October 7, 2017, in Goa. Fondly called '#ChaySam', they were one of the most-loved celebrity couples of Telugu.She tasted her first commercial success with Jr NTR-starrer Brindavanam and followed it up with yet another blockbuster, Dookudu featuring Mahesh Babu in the lead.She then proved her mettle as an actor with an amiable screen presence with SS Rajamouli's fantasy action film Eega (Naan Ee in Tamil).Her performance as the sensitive Nithya in Gautham Menon's Yeto Vellipoyindhi Manasu (Neethaane En Ponvasantham in Tamil) earned her immense praise and popularity.Being proficient in Telugu and Tamil, Samantha has become one of the busiest actors who has successfully balanced her career in both the languages.Samantha played a special cameo in the Hindi remake of Ye Maaya Chesave titled Ekk Deewana Tha (2014).She also signed an action-adventure comedy titled Assi Nabbe Poorey Sau in Hindi, alongside Aditya Roy Kapur. However, the film was later shelved due to various reasons.She also holds the distinction to share screen space with almost all the big stars from across industries.Samantha will be making her digital debut with Amazon Prime's The Family Man Season 2. She is said to play a negative role of that of a terrorist in the action drama web series, created by Raj and DK.After Anushka Shetty and Nayanthara, Samantha remains to be the only actor to have created a market for women-centric films, with films like U Turn, Oh Baby and Super Deluxe.Samantha stoked a controversy after she called the promotional poster of 1-Nenokkadine, which shows its leading lady Kriti Sanon crawling behind actor Mahesh Babu along a beach, 'deeply regressive'She again courted controversy for revealing actor Akhil Akkineni's presence in Manam (2014) and for retweeting a pirated image from her film 10 Endrathukulla (2015).Samantha is also a philanthropist and has started her own NGO, Pratyusha Support, to provide medical assistance for women and children.In 2017, Samantha was appointed as the ambassador for Telangana Handlooms by the government of Telangana and she currently works to promote handloom textiles in the State.