Samantha then worked on Gautham Menon's trilingual romantic drama film, and played the leading female role of Nithya in the Tamil, Telugu and Hindi versions of the film, shooting scenes simultaneously back-to-back with three different actors. The Tamil version, Neethane En Ponvasantham (2012) featured her alongside Jiiva, while Yeto Vellipoyindhi Manasu (2012) paired her opposite Nani. A further Hindi version titled Assi Nabbe Poorey Sau with Aditya Roy Kapoor was simultaneously shot with the other two films and was "sixty percent" completed, before Menon shelved the venture after his other Hindi film, Ekk Deewana Tha, had failed at the box office. The film spanned three periods in the life of a couple, focusing on their romantic relationship at school, college and in their late twenties. Samantha revealed that she knew Gautham would want to work with her again and immediately accepted the opportunity to portray the roles when she was offered the film. She felt that she "could relate to the attributes and the circumstances the character goes through" and described Nithya's character as "close to her". To make her performance as authentic as possible, Samantha chose to dub for herself in the Tamil version of the film. The Tamil and Telugu versions of the film opened in December 2012, earning differing reactions. Neethane En Ponvasantham earned mixed reviews and performed averagely at the box office, though Samantha received highly positive 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". Meanwhile, IBN stated "Samantha's transformation from a school kid to an adult is a treat to watch," while Rediff.com noted she is "pretty, graceful, and does an excellent job of conveying the emotions of a girl in love, especially during the school sequence, while concluding she carries the film on her slender shoulders." The Telugu version, Yeto Vellipoyindhi Manasu, won positive reviews and did well commercially, while Samantha's performance was equally well appreciated. The Hindu wrote she "goes a step further from her famous portrayal of Jessy (Ye Maaya Chesaave) and brings out the intricacy of her character well", while the Times of India wrote "Samantha has the author backed role and she creams it." At the Filmfare Awards ceremony celebrating South Indian films of 2012, the actress subsequently won the Best Actress awards for both the Tamil and Telugu film industries for her performances in Neethane En Ponvasantham and Eega. Samantha became the second ever actress to achieve the feat after Revathi had secured both awards in 1992. 2012 became her most prolific award-winning year and she secured further recognition for Best Actress at the Vijay Awards, Santosham Film Awards and the CineMAA Awards.
Samantha suffered from an extended period of illness in 2012, which saw her having to opt out of big film projects and take a two-month break from acting. She suffered from an immunity disorder and then had a further setback after her body did not respond well to antibiotics. She began dating actor Naga Chaitanya in 2010 and the pair were engaged in a ceremony in Hyderabad during January 2017. She got married in Goa as per traditional Hindu customs on 6 October 2017 and then by Christian customs on 7 October 2017.
Samantha has actively been involved in philanthropic activities and donates her earnings from endorsements, product launches and inauguration events to her charitable trust, Pratyusha Support, which was registered in 2012. She chose to begin the non-governmental organisation after being bed-ridden for 15 days during her documented illness in 2012, and wanted to give back to society. Samantha subsequently started the Pratyusha Support foundation to provide medical support for women and children with the help of three doctor friends, and provided the entire financial support for the programme. She held a fund raiser in August 2013 to raise awareness of her foundation, auctioning several of her personal items and memorabilia from films. A further initiative in 2014 saw the launch of a programme to fulfil the wishes of children with life-threatening diseases, with Samantha financing trips for children to fly on an aeroplane and travel to the Taj Mahal, while also organising opportunities for children to meet their favourite film actors. Samantha has also been involved in spreading awareness of haemophilia, regularly taking part in events creating awareness of the disease.