Born to Pakistani parents in Northampton, England, she spent her childhood in United Arab Emirates where she moved along with her family at the mere age of two. During her stay in UAE, she attended British School in Abu Dhabi. However, Mishal also spent a brief period with her family in Saudi Arabia. However, Mishal came back to UK in order to complete her education in an institution called Cobham Hall situated at Cobham in Kent, England.

Her education was furthered when she attained a Master’s Degree in International and Comparative Law from European University Institute in Florence, Italy before studying law at New Hall in Cambridge. As far as her family is concerned, her father was a practicing doctor when the family stayed in United Arab Emirates and studied at Army Burn Hall College, located in Abbottabad. Husain’s grandfather had served as an army officer during the era of undivided Pakistan in the post of Private Military Secretary.

Husain gained her first experience of journalism at the age of 18, spending three months as a city reporter in Islamabad, Pakistan, at the English-language newspaper The News. Then, while at university, she did several stints at the BBC as work experience.

Her first job was at Bloomberg Television in London from 1996, where she was a producer and sometime presenter. Two years later, in 1998, she joined the BBC as a junior producer in the newsroom and for the News 24 channel, and then in the Economics and Business Unit. Within a few months she moved in front of the camera and has since worked in a variety of roles: on the daily Breakfast programme, on Asia Business Report (based in Singapore), and as a presenter of business news on both BBC World News and the BBC News Channel. From September 2002 she was the corporation's Washington correspondent, serving as the main news anchor through the buildup to the invasion of Iraq and during the war.

She has interviewed many high-profile figures including Paul Wolfowitz, Deputy US Secretary of State Richard Armitage, Pentagon adviser Richard Perle, Rwanda's President Paul Kagame and Zimbabwe's President Emmerson Mnangagwa.

In 2011, Husain hosted Impanct on BBC World News, but in spring and summer 2011 she was engaged on making a documentary on the Arab Spring, for airing in the autumn of 2011. She presents the Sunday evening editions of the BBC Weekend News on BBC One. On 8 May 2010, she published an autobiographical essay in The Independent based on a nostalgia trip to the UAE. Husain is also a relief presenter of the BBC News at Six  and BBC News at Ten . She has occasionally presented Newsnight on BBC Two.

On 2 December 2011, it was announced that Husain would be part of the BBC's Olympic Presenting team. On 7 November 2013, it was announced that Husain would be part of the BBCs Commonwealth Games Presenting team. On 17 March 2013 she presented the last News at Ten to be broadcast from BBC Television Centre.

On 16 July 2013, the BBC's Director-General Lord Hall announced that Husain was to become a presenter of BBC Radio 4's Today programme in the autumn. She continues to present the Sunday evening editions of the BBC Weekend News on BBC One and on occasions on BBC World News and the BBC News Channel.

Husain presented her first edition of Today on 7 October 2013, when her co-presenter was John Humphrys. Husain won the Broadcaster of the Year Award at the London Press Club Awards in 2015.

On 27 November 2017, she recorded an interview on behalf of all journalists with the newly engaged Prince Harry and Megan Markle. It was first aired at 6pm.

Mishal Husain joined the Today presenting team in October 2013.