Her great-grandfather, Fazl-e-Haq Khairabadi, a scholar of Islamic studies and theology, edited the first diwan of Mirza Ghalib on his request and later became a figure during the Indian Rebellion of 1857 in his native Khairabad.

[6] Akhtar made her directorial debut with the drama Luck By Chance (2009), starring her brother Farhan and Konkona Sen Sharma in lead roles.

It opened to widespread critical acclaim, with high praise directed towards its novel concept, story, screenplay and dialogues; however, the film had an underwhelming performance at the box-office.

In 2011, she achieved her breakthrough with the coming-of-age comedy-drama Zindagi Na Milegi Dobara, which stars an ensemble cast of Hrithik Roshan, Farhan Akhtar, Abhay Deol, Katrina Kaif and Kalki Koechlin in lead roles.

It emerged as a major commercial success at the box-office, grossing ₹1.53 billion (US$19 million) worldwide, ranking as the fifth highest-grossing Hindi film of the year.

[13][14] Her segment titled Sheila Ki Jawaani, told the story of a 12-year-old child who idolised Hindi film actress Katrina Kaif and aspires to be a Bollywood dancer, earned her positive reviews from critics.

The film stars an ensemble cast, with Anil Kapoor as an egotistical industrialist, Shefali Shah as his bitter socialite-wife, and Priyanka Chopra and Ranveer Singh as their children.

In 2018, she again teamed up with Kashyap, Banerjee and Johar for the anthology film Lust Stories, the sequel to Bombay Talkies, which premiered on Netflix in June 2018.

[20] It received positive reviews from critics upon release, and emerged as a commercial success at the box-office, grossing ₹2.38 billion (US$33.8 million) worldwide, ranking as the ninth highest-grossing Hindi film of the year.

The same year, Akhtar and Kagti created the romantic comedy-drama web series Made in Heaven, alongside Nithya Mehra and Alankrita Srivastava which told the story of two wedding planners in New Delhi.

[22][23] The series, which stars an ensemble cast of Arjun Mathur, Sobhita Dhulipala, Jim Sarbh, Shashank Arora, Kalki Koechlin and Shivani Raghuvanshi in lead roles, was produced by Tiger Baby Films and Excel Entertainment, and premiered on Amazon Prime Video.

In 2023, she and Kagti co-created the crime thriller web series Dahaad starring Sonakshi Sinha, Gulshan Devaiah, Vijay Varma and Sohum Shah in lead roles.

[27] The film stars debutants Agastya Nanda, Khushi Kapoor, Suhana Khan, Vedang Raina, Mihir Ahuja, Aditi Saigal and Yuvraj Menda as Archie Andrews, Betty Cooper, Veronica Lodge, Reggie Mantle, Jughead Jones, Ethel Muggs and Dilton Doiley respectively.