Over the next few years, she played the leading lady in top-grossing androcentric films such as Dookudu (2011), Seethamma Vakitlo Sirimalle Chettu (2012), Attarintiki Daredi (2013), Kaththi (2014), Theri (2016), 24 (2016), Mersal (2017), and Rangasthalam (2018).

The film, simultaneously made in Tamil as Vinnaithaandi Varuvaayaa (2010), was highly anticipated prior to release, primarily due to the first time collaboration between Gautham Menon and composer A. R.

[14] Post-release, she revealed that Menon played a "crucial part in moulding her as an actress", teaching her how to remain natural and comfortable in front of the screen, even if she had no dialogues in a scene.

[30] The film received positive reviews, with a critic from The Times of India stating "Samantha looks beautiful and has done a great job, though her role as Prashanthi isn't too lengthy.

[32] During the period, Samantha had also been signed two big-budget projects in Tamil, Mani Ratnam's Kadal (2013) and Shankar's I (2015), but was forced to opt out from both films, since she was suffering from a skin disease and could not work for two months during mid-2012.

[33][34][35] Samantha next featured in S. S. Rajamouli's live action Telugu-Tamil bilingual project Eega (2012) alongside Nani and Sudeep, portraying a micro artist who runs a NGO and takes revenge for the murder of her lover.

Neethane En Ponvasantham earned mixed reviews and performed averagely at the box office, though Samantha received highly critical acclaim for her portrayal.

The critic from The Hindu noted she "comes up with possibly the best performance by a female lead in Tamil cinema this year" and "her transformation from a gawky teenager to an adult, unable to overcome her ego, is outstanding".

[54] Samantha next appeared in the Telugu multi-starrer film, Seethamma Vakitlo Sirimalle Chettu (2013) alongside Venkatesh and Mahesh Babu, which received positive reviews and was commercially successful.

[55][56] The romantic comedy Jabardasth (2013) alongside Siddharth, in which she portrayed a wedding planner, became a commercial failure, though critics noted Samantha is "getting better by the day and it's a delight to watch her on screen".

Samantha subsequently featured alongside Naga Chaitanya again in the long-delayed Autonagar Surya (2014), before playing different minuscule roles in the Telugu action masala films Alludu Seenu (2014) and Rabhasa (2014).

"[63][64] Samantha later revealed that she solely worked on Alludu Seenu as a favor to producer Bellamkonda Suresh, who had helped her delay the making of Jabardasth during her health problems.

[citation needed] Again, reviewers criticised her character stating "all she had to do in the film is smile and look pretty," while The Hindu remarked she played "an emoticon" and "that covers her contribution to the proceedings".

She sported a different rural look for the role and her performance won mixed reviews, with a critic noting "Samantha doesn't make much of an impact in the film except towards the end.

Her performance received positive reviews, with a critic from DNA India stating "Samantha looks pretty as always" and that "she has done an incredible job in dubbing with a range of emotions in her numerous shades – doctor, lover, mother – and she shines".

Samantha also featured in three high-profile Telugu films during 2016; Although Srikanth Addala's family drama Brahmotsavam opposite Mahesh Babu was a box office failure, her role in Trivikram Srinivas's romantic comedy, A Aa alongside Nithiin, won her high critical acclaim and commercial success.

A critic from The New Indian Express noted "A Aa undoubtedly is Samantha's film" and that "right from her first frame till the last, she delivers a stellar performance and shows what she can do if given ample screen time", adding that she was "a joy to watch".

She then featured in the commercially successful action film Janatha Garage directed by Koratala Siva, with a critic noting despite "a limited role, she gives a nice performance".

[94] The Tamil action thriller Irumbu Thirai in which she starred opposite Vishal and the Telugu biographical drama Mahanati were successful at the box-office and each had a run of 100 days at the box office.

Mridula R from The News Minute noted her critically acclaimed film U Turn as a curiosity-generating script that provides her with the ultimate screen presence since the story begins with her and she finds it ends, rather that not being shaking a leg in Anjaan, Brindavanam, Kaththi and Attarintiki Daredi or being glam doll or having out-of-scope performances overshadowed in Dookudu, S/O Satyamurthy, Brahmotsavam, Theri and Mersal.

[97] Manoj Kumar R of The Indian Express felt that Samantha thrives in the role that reflects the possibilities of youth, the burden of old age, and the society's indifference to the desires and complaints of old people.

[106] In 2021, Samantha headlined the second season of Amazon Prime Video's Hindi spy thriller streaming television series The Family Man alongside Manoj Bajpayee, thus marking her debut in the digital content medium.

[157] Her initial choice of films depicted her as an actress who actively selects to feature in strong female roles, with The Times of India noting that "scripts are written around the characters she portrays" and that she held a place in the "wishlist of every top actor, director and producer".

[158] Her inclusion in Telugu film projects were also initially considered a "lucky charm" by producers, though Samantha acknowledged that though "destiny" played a role in her career, and that there were "many women out there who are more beautiful and more talented" than she was and that she hoped her name would instead be "synonymous with hard work".

When questioned on her decision not to take up more heroine-oriented roles, Samantha lamented the lack of chances that the South Indian film industry presents for established female characters and described it as "simply male-dominated".

[165] She has often been cast opposite the same actors more than once, featuring in two or more films with Vijay, Suriya, Naga Chaitanya, Nani, Mahesh Babu and N. T. Rama Rao Jr., a feat Samantha revealed she takes "pride in".

[169] The tweet received an adversely storming response from Mahesh Babu's fans, who launched a scathing attack on her online and targeted abuse at the actress.

Her opinions were later backed by actor Siddharth and directors Sekhar Kammula and Nandini Reddy, who also resultantly faced similar abuse, before Mahesh Babu apologised.

[173][174] Her family home in Chennai was raided in late September 2015 by income tax officials, in a planned operation targeting film actors, though the actress and her father denied making any wrongful payments.

[178][179] Condemning her, Cyriac Abby Philips, a hepatologist, called her "health and science illiterate" claiming that such methods are dangerous for lungs while providing evidences and journals for reference in his post on X.