Seema Mustafa was born in Delhi on to a muslim family hailing from Uttar Pradesh with long-standing connections to the Congress party. Her father, Lt. Col. Syed Mustafa, was an officer in the Indian Army. Her mother was the daughter of Shafi Ahmed Kidwai, brother of Rafi Ahmed Kidwai, a noted freedom fighter and Congress politician. Shafi Ahmed Kidwai, who lived in Mussoorie, was killed in 1947, at the time of the partition of India. His wife Anis Kidwai (Seema's maternal grandmother) was later made a Rajya Sabha MP belonging to the Congress party.
Seema has two elder brothers, S.P. Mustafa (known as "Bobby"), group treasurer of Hindustan Unilever, and Kamal Mustafa, now retired but formerly the Head of Global M&A of Citibank.
Seema graduated with a BA in Political Science from Lucknow University in Uttar Pradesh. During her college days, she met and married a Hindu businessman R.P Singh and had two children, a son Agneya Singh and a daughter Gayeti Singh.
Seema Mustafa began her career in journalism with The Pioneer (a Lucknow-based newspaper), moved to The Patriot in 1979, and worked for several other Indian publications, including The Telegraph and Indian Express before joining the Asian Age in 1997 as its political editor and Delhi bureau chief.
While with the Asian Age, Seema received the prestigious "Prem Bhatia Award for Excellence in Political Reporting and Analysis" in 1999 for her coverage of the Kargil war. She also wrote a weekly op-ed column which was syndicated to several other newspapers, including The Deccan Chronicle of Bangalore and The Dawn, a Pakistani newspaper. In 2008, she wrote an op-ed that was uncharacteristically critical of the Congress party. The article denounced the Indo-US Nuclear Deal specifically and the congress-led government in general for seeking friendly relations with the George W. Bush administration. The column characterized the Bush administration and the "muslim world" as being at war with each other and threatened revolt by Indian muslims if the Indian government sided with the US by signing any nuclear agreement with the US government, regardless of the benefit to India. Although the intemperance of her views and language elicited criticism in the Indian media, MJ Akbar, founding editor of the Asian Age, defended Seema strongly and the newspaper propogated the same views as hers on its pages. Ultimately, M.J. Akbar and Mustafa were both sacked from the Asian Age.
After leaving the Asian Age in 2008, Seema worked as Resident Editor of Covert, a fortnightly left-wing political magazine. In January 2010, her mentor M.J. Akbar launched The Sunday Guardian, a weekly newspaper, and Seema joined him as Resident Editor. By September the same year, the publication was on its last legs and was acquired by the ITV Group, which runs the India-TV and NewsX television news channels. After the sale, Akbar moved to the India Today group, while Seema moved to NewsX, hosting a weekly interview programme named Straight Talk With Seema Mustafa on that channel. The program did not get enough TRPs (viewership), and Seema moved on again.
She next took over the job of Director of a new, left-wing and Muslim-oriented think-tank based in New Delhi named the "Centre for Policy Analysis"  (not to be confused with the eminent Delhi-based think-tank, the Centre for Policy Research), a position she presently holds. Concurrently, in January 2014, She founded The Citizen, an independent "Digital Daily" based out of New Delhi.
Seema has been noted for having a characteristic leftist and socialist perspective, apart from her almost helpless championing of the "muslim viewpoint" on any and all matters. Her articles invariably reflect the communist, feminist and pro-minority slants on any issue.
Seema has been associated with several communist and socialist political parties since the 1980s. She wrote the authorised biography of former prime minister VP Singh, entitled The Lonely Prophet, and was closely associated with him during his lifetime. She was a member of his party, the Janata Dal, for many years. She once contested the UP provincial assembly elections as a Janata Dal candidate but lost.
Seema also contested parliamentary elections to the Lok Sabha two times (1991 and 1996) from the Domariaganj constituency in Uttar Pradesh, but lost badly and even forfeited her election deposit on both occasions. In the 1991 elections, she took the 4th position in 1991 and in 1996, the 10th position. In 1991, she contested as a candidate of the Indian Congress (Socialist) - Sarat Chandra Sinha, an obscure splinter of the Indian National Congress (Socialist), itself a splinter of the Congress party. In 1996, she contested as an independent candidate.
In 2012-13, Seema associated herself with the Communist Party of India (Marxist) (CPM) in its campaign to pressure the government of India to oppose the USA and support Iran on the issue of Iran's right to develop nuclear weapons. Seema is part of the CPM's Committee to Campaign for an Independent Foreign Policy. She has of course written extensively in opposition to the Indo-US Nuclear Agreement.Mustafa, Seema (1995). The Lonely Prophet: V.P. Singh, a Political Biography. New Delhi: New Age International. ISBN 978-81-224-0809-6. OCLC 33664491.
Mustafa, Seema; Anuradha M. Chenoy and Initiative for National Renewal and Empowerment of the People (1995). The Scam: The Cover-up and Compromise. New Delhi: Wiley Eastern. ISBN 978-81-224-0713-6. OCLC 32698384.
Mustafa, Seema (2012). Azadi's Daughter: Journey of a Liberal Muslim. New Delhi: ImprintOne. ISBN 978-81-888-6115-6.
Mustafa, Seema (2013). Journalism: Ethics and Responsibilities. New Delhi: Pragun Publications. ISBN 978-81-241-1780-4.