In 2011, she directed Zindagi Na Milegi Dobara, which starred an ensemble cast of Hrithik Roshan, Farhan Akhtar, Abhay Deol, Katrina Kaif and Kalki Koechlin. It turned out to be a huge commercial success at the box-office and won her the Filmfare Award for Best Director.

In 2013, Akhtar teamed up with Anurag Kashyap, Dibakar Banerjee and Karan Johar for Bombay Talkies. It was made as a celebration of 100 years of Indian cinema. She then went on to direct Dil Dhadakne Do (2015), a film based on a dysfunctional Punjabi family starring Anil Kapoor as an egotistical industrialist, Shefali Shah as his bitter socialite-wife, and Priyanka Chopra and Ranveer Singh as their children. The film also featured Anushka Sharma and Farhan Akhtar as love interests for Ranveer Singh and Priyanka Chopra respectively.

In 2018, she then again teamed up with Anurag Kashyap, Dibakar Banerjee and Karan Johar for Lust Stories, which premiered on Netflix in June 2018.

As of October 2019, she is directing a segment of Ghost Stories (2020), an horror anthology film, consisting of 4 short film segments. Other segments are directed by Anurag Kashyap, Dibakar Banerjee, and Karan Johar. Ghost Stories premiered on Netflix on 1 January 2020.

She appeared on the Valentine’s Day charity show of Kaun Banega Crorepati along with her brother Farhan Akhtar. She also appeared in a very brief role as Rasa Devi’s (Rekha’s) courtesan in Kama Sutra: A Tale of Love. She and Shah Rukh Khan had a ‘fireside chat’ with Jeff Bezos of Amazon in January 2020.