Inspired by Indira Gandhi, Heptulla joined the 'Indian National Congress' party in 1980. She soon rose to prominence in the party. In 1986, she became the general secretary of the party (1986–1987). She also served as the spokesperson (1986–1987 and 1998) of the party and managed the youth activities of the 'All India Congress Committee' and the 'National Students' Union of India' (NSUI), the student wing of the party.
Heptulla served as the deputy chairperson of the 'Rajya Sabha' twice: first, from January 1985 to January 1986, and then from 1988 to July 2004.
She has been a strong advocate of women empowerment. In 1992, she presided over the 'Conference of Women Parliamentarians' of the 'Commonwealth Parliamentary Association' in New Delhi. Three years later, she represented India in the fourth 'World Conference on Women' in Beijing.
In 1993, Heptulla became the founder-president of the parliamentarians' forum for human development and headed the women parliamentarians' group of the 'Inter-Parliamentary Union,' a Geneva-based global inter-parliamentary institution. Between 1995 and 1999, she served in the executive committee of the council. In 1997, she presided over a group of ‘U.N. Commission’ delegates on the “Status of Women.”
That year, she attended the 'International Women's Leadership Conference' at 'Harvard University,' Cambridge, Massachusetts.
At the council's 165th session held in Berlin in October 1999, she was appointed as the president of the organization. She continued in the post till September 2002. During the council's 171st session, she was named the “Honorary President of the Council.”
Heptullah has also served as the prime minister's special envoy on foreign visits, especially to the Middle East. She was nominated to preside over the 'Indian Council for Cultural Relations' (ICCR). She was nominated as the 'United Nations Development Programme' human development ambassador.
Heptulla stirred a controversy when she was accused of morphing a photograph clicked in 1958, to show renowned freedom fighter Maulana Abul Kalam Azad beside her. The photo was later published in an ‘ICCR’ publication titled 'Journey of a Legend,' based on the life of Azad. Noted scholar Maulana Azad, the country's first education minister, was also the first chairperson of the ‘ICCR.’
The photograph was published with the caption "Najma Heptulla with Maulana Azad after her graduation." The ‘ICCR Employees Association' president filed a public interest litigation at the ‘Delhi High Court.’ The court eventually commissioned the ‘CBI’ for investigation. The photograph was subsequently proved to be fake, as Heptulla had graduated in May 1958, while Azad had died on February 22 that year.
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The ‘ICCR’ later withdrew the publication and released a revised version without the controversial photograph.
Following her strained relationship with 'Congress' president Sonia Gandhi, Heptulla quit the party and joined the 'Bharatiya Janata Party,' or the ‘BJP,’ in 2004. She later claimed that Sonia Gandhi had humiliated her. She also indicated that her differences with the party's leadership and ideologies were the reasons for her exit.
From July 2004 to July 2010, Heptulla represented the Indian state of Rajasthan as a ‘BJP’ member in the 'Rajya Sabha.'
In 2007, the ‘BJP’-led 'National Democratic Alliance' (NDA) nominated her in the then-upcoming election for the vice-president. However, she lost the election to Hamid Ansari.
In 2010, when the party was presided by Nitin Gadkari, Heptulla became a ‘BJP’ vice-president.
In 2012, she was again elected to the 'Raya Sabha,' from Madhya Pradesh. She assumed office in April that year and continued till August 20, 2016. However, by 2013, her position in the ‘BJP,’ under the new leadership of Rajnath Singh, began to decline. In March that year, she stepped down as the party's vice-president and was appointed as the party's national executive.
From May 26, 2014, to July 12, 2016, Heptulla was appointed to the ministry of minority affairs in the new cabinet of Prime Minister Narendra Modi. She supported the minorities, referring to them as a significant part of the Indian society. She, however, opposed minority reservation, as she believed it hampered the competitive spirit of people.
In her first term as the minority affairs minister, Heptulla made a controversial speech, calling all Indians "Hindus." She later clarified her statement, saying that ''Hindi'' was the Arabic term for people with Indian nationality and that the term was not in any way related to the religion.
She quit as the minority minister in 2016 and subsequently became the governor of the state of Manipur. The following year, she was appointed as the 11th chancellor of 'Jamia Millia Islamia,' a central public university in New Delhi, India.
Heptulla is the author of the book 'AIDS: Approaches to Prevention.'
Her other written or edited publications are 'India's Progress in Science and Technology: Continuity and Change' (1986), 'Indo-West Asian Relations: The Nehru Era' (1991), and 'Reforms for Women: Future Options' (1992).