Her father, Hafeez Khan, migrated to the newly formed country after Partition in 1947. Mahira's younger brother, Hassan Khan, is a journalist. The actress married Ali Askari in 2007 and had a son. They were divorced in 2015.

Mahira Khan did her schooling from the Foundation Public School, Karachi, and then went to California to pursue further studies at the Santa Monica College, Los Angeles, and the University of Southern California. However, she had to give up her education midway and she returned to Pakistan in 2008. While studying, she also worked as a cashier at a Rite Aid store in Los Angeles.

Mahira Khan began her career as a VJ for the show Most Wanted on MTV Pakistan in 2006. In 2008, she hosted Aag TV's reality show Weekends With Mahira.

She made her acting debut on the big screen with the Pakistani Urdu social drama Bol (2011). The film was successful at the box office. The same year, she played the lead in the Pakistani drama Neeyat aired on the ARY Digital channel.

Mahira Khan gained immense popularity with her portrayal of Khirad Ashar Hussain in Sarmad Sultan Khoosat’s television drama series Humsafar on Hum TV (Pakistan) and Zindagi TV channel (India). Her next TV shows were Shehr-e-Zaat, the talk show The Lighter Side Of Life and Sadqay Tumhare.

In 2015, she appeared in the biographical Pakistani film Manto and the Pakistani romantic drama Bin Roye. She won several awards for her performance in Bin Roye. The following year, she starred in the television adaptation of the film. She then played the lead in the Pakistani coming-of-age drama Ho Mann Jahaan.

Mahira Khan made her debut in Indian cinema with the crime action film Raees (2017) starring Shah Rukh Khan. The same year, she played a rape victim in the Pakistani film Verna. In 2018, she starred in the romantic comedy 7 Din Mohabbat In.

Among Mahira Khan’s upcoming films is Bilal Lashkari's action drama Maula Jatt 2.

Over the years, Mahira Khan has won many awards for her performances. These include the Lux Style awards for Best Actress for Bol, Humsafar, Bin Roye, Sadqay Tumhare, Ho Mann Jahaan and Verna. She has also won the Pakistan Media award for Shehr-e-Zaat, the Hum award and the Hum Style award.