Yami Gautam made her Bollywood debut with a leading role in Shoojit Sircar's romantic comedy-drama Vicky Donor (2012). Co-starring opposite Ayushmann Khurrana and Annu Kapoor, she portrayed Ashima Roy, a Bengali woman who falls in love with a Punjabi (Khurrana) and gets to know about his past after marriage. The film, which marked Bollywood actor John Abraham's production debut, received positive reviews from critics and proved to be a major commercial success and one of the highest-grossing films of the year with worldwide grossing of ₹645 million. For her debut performance, Gautam received critical appraisal as well as several awards and nominations, including the Best Female Debut (tied with Ileana D'Cruz for Barfi!) trophy at the Zee Cine Awards, and a nomination under the same category at the 58th Filmfare Awards.

After a two-year absence from Bollywood films, Gautam returned in 2014 and appeared in two films, the first of which was Eeshwar Nivas's romantic comedy film Total Siyappa, co-starring Ali Zafar, Anupam Kher, and Kirron Kher, in which she played the love interest of Zafar's character.

In 2016, Gautam played Pulkit Samrat's love interest in two romances–Divya Khosla Kumar's Sanam Re and Vivek Agnihotri's Junooniyat. In the former, she played a high-school girl who falls in love with Samrat's character, and in the latter, she portrayed a Punjabi girl who falls in love with an army officer (Samrat). Both Sanam Re and Junooniyat were commercial failures.

The following year, Gautam collaborated with Hrithik Roshan on Sanjay Gupta's revengeful romantic thriller Kaabil (2017), which tells the story of a blind man who avenges the rape of his blind wife. The film, as well as her performance, received mixed reviews and the film emerged as financial success, earning ₹1.96 billion (US$28 million) worldwide. Later in 2017, Gautam featured briefly in Ram Gopal Varma's political thriller Sarkar 3, the third installment of Varma's Sarkar franchise, alongside Amitabh Bachchan, Jackie Shroff, Manoj Bajpayee, and Amit Sadh. Sarkar 3 failed to do well at the box office. Gautam's next release was the Shree Narayan Singh directed-social problem dramedy Batti Gul Meter Chalu (2018), in which she played a lawyer alongside Shahid Kapoor, Shraddha Kapoor, and Divyendu Sharma. The film was also unsuccessful at the box office.

Gautam's greatest success came in 2019 when she appeared in Aditya Dhar's military action thriller film Uri: The Surgical Strike, alongside Vicky Kaushal, Paresh Rawal, Mohit Raina, and Kirti Kulhari. Based on the 2016 Uri attack, Gautam portrayed Pallavi Sharma, a nurse-turned-an intelligence officer.

She reunited with Ayushmann Khurrana in Amar Kaushik's comedy-drama Bala, a satire on physical attractiveness, which was released on 7th November 2019. The Movie was released and emerged as a commercial succes and the performance of Yami Gautam as Pari was praised by critics. As of January 2020, Gautam has one upcoming film. She is currently doing a film known as Ginny Weds Sunny opposite Vikrant Massey directed by debutant Puneet Khanna and produced by Vinod Bachchan.