After a brief modelling career, Mandanna made her acting debut with the Kannada romantic comedy Kirik Party (2016), and found further commercial success in the action picture Anjani Putra and romance Chamak (both 2017).

[3][4] As a child, her family struggled financially, and had difficulties finding a home and paying rent; according to Mandanna, her parents could not afford to buy her toys and the experience has continued to taint her relationship with money.

[7] Mandanna studied for a bachelor's degree in psychology, Journalism and English Literature at M. S. Ramaiah College of Arts, Science and Commerce in Bangalore.

[21] In the former, The Indian Express noted that she had been reduced to "a hero's arm candy", but in the latter, Firstpost's Karthik Kermalu commended Mandanna for enhancing a mediocre picture.

[26] In mixed reviews of the film, Hemanth Kumar of Firstpost lauded her "terrific debut" and Stivathsan Nadadhur from The Hindu appreciated her comic timing.

[36][37] The Kannada social action film Yajamana (2019) had a mixed reception from critics, with Karthik Keramalu particularly criticising the significant age gap between Mandanna and Darshan.

[40] She then reunited with Deverakonda for the Telugu romantic drama Dear Comrade, in which she played Lilly, an aspiring cricket player who faces sexism and discrimination from within the sport.

[42] It also marked a departure from the mostly light-hearted parts she had portrayed before and, in preparation, she underwent five months of "rigorous physical training" to authentically emulate the body language of a cricket player before filming commenced.

[50] Her role, however, was poorly received by critics;[51][52] Sangeetha Devi Dundoo of The Hindu bemoaned that her character did not offer her adequate scope to perform as "all she gets to do is fawn over Mahesh".

[61] Her final appearance of the year was in the critically and commercially successful Telugu action film Pushpa: The Rise, starring Allu Arjun.

[63] Film Companion's Mukesh Manjunath found that she did her "best to imbue bubbliness and the innocence required in these testosterone-charged surroundings" but lamented that the brown-facing of her character was "unnecessary and ineffective".

Citing it as one her better films, Sangeetha Devi Dundoo appreciated that Mandanna is "given the scope to play a self-centred character" and showed that she is willing to take on well-written roles.

[73] Against expectations, the film emerged as a success at the box-office and Mandanna earned her first nomination for Best Supporting Actress (Telugu) at the Filmfare Awards South.

[74][75] Initially set to debut in Hindi cinema with Mission Majnu, delays led Mandanna to instead make her first appearance alongside Amitabh Bachchan in Vikas Bahl's family drama Goodbye, as a career-driven woman who attempts to come to terms with the loss of her mother (played by Neena Gupta).

[76][77] She was initially hesitant to accept the role as she found it difficult to essay a character with dismissive views towards religious rituals, which significantly contrasted with her own faith in them.

[78] Though a box-office bomb, her performance was well received by Devesh Sharma of Filmfare who appreciated the subtlety she brought to her scenes and particularly her ability to "leave an impact even in this non-glamorous debut".

[85] Netflix's unremarkable Hindi spy thriller Mission Majnu featured Mandanna as a visually-impaired woman opposite Sidharth Malhotra, and marked her foray into streaming.

[86] Her performance was poorly received;[87][88] In a scathing review for Rediff.com, Sukanya Verma wrote that "Wearing a nose ring and smiling in response to everything is Rashmika's role in a nutshell".

[91][92] WION's Shomini Sen praised Mandanna for salvaging a poorly-written character that had been constrained by Vanga's focus on "a skewed version of an alpha male".

[93] Following criticism regarding her character's perceived complicity in allowing misogyny, Mandanna defended her role, stating that Geetanjali was "the only force at home holding her family together".

[98] The Indian Express's Anandu Suresh was displeased with the hypersexualisation of her role, and took note of a recurring theme in her filmography of playing the love interest of "unnervingly eccentric" men.

[99] Mandanna defended the representation of toxic masculinity in both the Animal and Pushpa franchises, explaining that such individuals exist in reality, and their hyperbolic depiction is a "cinematic liberty intended to entertain the audience".

[127] In December 2023, Delhi Police "communicated with Meta to obtain the URL ID associated with the account responsible for generating the video", and filed a First information report (FIR) in relation to the case.