Qureshi made her feature film debut with a supporting role in Anurag Kashyap's critically acclaimed two-part crime drama Gangs of Wasseypur – Part 1 (2012), where Qureshi was cast as the supportive wife of a criminal (played by Nawazuddin Siddiqui). She described her character as a small-town airhead who thinks she is the prettiest girl in the village: "Mohsina tries to copy everything she sees on the big screen in her own little ways. She is heavily influenced by Bollywood". The film premiered at the 65th Cannes Film Festival, and both the film and Qureshi received positive reviews from critics. Govind Nihalani noted her screen presence, comparing the actress to Smita Patil: "an earthiness, sincerity, intensity and warmth of personality, qualities that distinguished Smita, apart from the fact that she was a very fine and instinctive actress. Huma is a good enough actress on her own, someone who can stand apart from the crowd and hold her own". Taran Adarsh of Bollywood Hungama noted: "Huma Qureshi, who's introduced much later in the film...is wonderful". The Express Tribune added: "When it comes to looks, [Huma] is different from the typical Bollywood actors". In 2012, Qureshi was ranked third, the highest female position, on Rediff.com's annual list of "Bollywood's Top Ten Debutants" (male and female). Following the success of the first part, she reprised her role of Mohsina in the second instalment of the Gangs of Wasseypur series, Gangs of Wasseypur – Part 2. The film premiered in the Cannes Directors' Fortnight at the Cannes Film Festival with its prequel. It opened to wide critical acclaim, and her portrayal again received positive reviews. Madhureeta Mukherjee of The Times of India said: "Huma Qureshi, with her gaudy clothes, designer sun-glasses and unusual attractiveness is the hottest cheez in Wasseypur. She beautifully lends support as a powerful man's 'prouder' better-half, even in his worst crimes", and Taran Adarsh found her "simply fantastic". Both films earned her Best Female Debut and Best Supporting Actress nominations at several award ceremonies (including the Filmfare Award). Qureshi described Gangs of Wasseypur as a "life-changing film".

That same year, Qureshi completed her three-film contract with Anurag Kashyap Films by starring in Luv Shuv Tey Chicken Khurana, a romantic comedy, which describes a quest for an ancient family dish; Chicken Khurana. Directed by Sameer Sharma, she played the role of a feisty Punjabi girl, Harman (star Kunal Kapoor's love interest). The film was a financial success, and Rediff.com noted that "Huma Qureshi looks right for the role and she delivers a wonderful performance". Aniruddha Guha of the Daily News and Analysis said: "[Qureshi], on the other hand, is charming as the fiery Punjaban, Harman. Her refreshingly natural acting style impresses again in a role that has shades of her character in Gangs of Wasseypur". However, Anupama Chopra found her performance to be "a little bland".