Khan was born on 31 July 1954 to Brigadier (retired) Fateh Khan in Chakri village, Rawalpindi District. He attended Aitchison College and Army Burn Hall College. He was born in a family of Jodhra and Alpial tribes of Rajput.

He was first elected to the National Assembly in the 1985 general election from constituency NA-52 (Rawalpindi-III). He was re-elected to the National Assembly from the same constituency in the 1988 general election on the Islami Jamhoori Ittehad ticket. He was then appointed as the Federal Minister for Science and Technology. After getting re-elected for the third time to the National Assembly in the 1990 general election on the Islami Jamhoori Ittehad ticket from constituency NA-52 (Rawalpindi-III), Khan was made the Federal Minister for Petroleum and Natural Resources and Provincial Coordinator, where he served from 1990 to 1993 during the first government of Sharif. He was re-elected to the national assembly for the fourth time in the 1993 general election from constituency NA-52 (Rawalpindi-III).

After getting re-elected for the third time to the National Assembly in the 1990 general election on the Islami Jamhoori Ittehad ticket from constituency NA-52 (Rawalpindi-III), Khan was made the Federal Minister for Petroleum and Natural Resources and Provincial Coordinator, where he served from 1990 to 1993 during the first government of Sharif. At that time the president was Ghulam Ishaq Khan and he was also a close aid of him. At that time Sharif survived a serious constitutional crisis when President Khan attempted to dismiss him under article 58-2b, in April 1993, but he successfully challenged the decision in the Supreme Court. Sharif resigned from the post, after which all ministers were resigned and Nishar was also removed for the second time from his ministry without completing his whole term.

He was re-elected to the National Assembly for the fifth time in the 1997 general election from constituency NA-52 (Rawalpindi-III) and was for the second time appointed as the Federal Minister for Petroleum and Natural Resources, where he served until he was dismissed in October 1999 after the coup d’état when then Chief of Army Staff, Pervez Musharraf, overthrew the elected government of Sharif. Khan was placed under house arrest for many weeks. It was during his tenure as Member of the National Assembly, he became the most powerful man in PML-N after Nawaz Sharif. Khan was also among Sharif’s loyalists who kept the PML-N alive during the Musharraf rule. Musharraf was reportedly appointed as the Chief of Army Staff on the recommendation of Khan.

Khan was re-elected to the National Assembly for the sixth time in the 2002 general election from constituency NA-52 (Rawalpindi-III). However, he lost the election in constituency NA-53 (Rawalpindi-IV).

He was re-elected as a member of the National Assembly in the 2008 general election for the seventh time, both from constituency NA-52 (Rawalpindi-III) and from constituency NA-53 (Rawalpindi-IV). Later, Khan vacated the NA-52 seat and retained NA-53.

Khan was appointed as the Federal Minister for Food, Agriculture and Livestock and Federal Minister for Communications in March 2008 in the government of Yousaf Raza Gillani, but his tenure was short-lived due to PML-N’s decision to leave the Pakistan Peoples Party-led coalition government.

In September 2008, he was appointed as the Leader of the Opposition in the National Assembly after the resignation of Chaudhry Pervaiz Elahi. In October 2011, he became the first-ever chairperson of the Public Accounts Committee of the National Assembly (which was created to audit the accounts of the government) to present annual reports, but he resigned in November 2011 claiming that accountability was not possible under the Pakistan Peoples Party regime led by President Asif Ali Zardari and Prime Minister Gilani.

Nisar was appointed at position of 3 Ministries under Yousaf Raza Gillani, when he was the face of PML (N) in 2008 Pakistani general election and remained for a short period of 2 months(from 31 May 2008 – 14 March 2008) as the party was in alliance with Pakistan Peoples Party, and at that time Nisar openly blamed Pervez Musharraf and PML (Q) over weak Law and Order. He was assigned 3 ministries:-

Despite being perceived as anti-American, a contradictory version of Khan’s political views surfaced in a US diplomatic cable which was leaked by WikiLeaks in 2011. The cable, which was sent by the former United States Ambassador to Pakistan, Anne W. Patterson, in September 2008 reads: “As always, Nisar insisted that he and the PML-N were pro-American (saying that his wife and children in fact are Americans).” Khan clarified that he was not against the American nation, but was opposing the US policy towards Muslims after the 9/11 attacks.

For the 2013 general election, Khan was made part of PML-N’s central parliamentary board tasked with selecting candidates for the election. Khan was re-elected to the National Assembly from constituency NA-52 (Rawalpindi-III) for the eighth time in the election and was appointed as the Federal Minister for Interior and Narcotics Control in the Sharif cabinet, as he had a close relationship with the Pakistan Armed Forces.

In 2013, Dawn reported that, although Khan had no post in PML-N, he was known for his assertiveness in the party’s affairs and had had differences with other PML-N leaders. Reportedly, before the 2013 election, Khan lobbied to become the Chief Minister of Punjab, Pakistan, and proposed that Shehbaz Sharif be made Minister for Water and Power, but Nawaz Sharif did not give the party ticket to Khan for the provincial seat. In spite of that, Khan contested the election for provincial assembly seat as an independent candidate and won. Dawn reported that Khan was once considered the de facto chief minister of Punjab.

Nisar was appointed as the 34th Minister of Narcotics Control and Minister of Interior under the Third Nawaz Sharif Ministry in the year 2013, when Pakistan Muslim League (N) made the government in 2013 Pakistani general election. Nisar who was Leader of Opposition from 2008-2013 was appointed as the Minister and sworned for the position on 11 May 2013. He was preceded by Malik Habib and remained in the office for 4 years till 2017, after when Nawaz Sharif resigned from the position of Prime Minister due to Corruption charges and the government fell down.

In March 2015, The News International commended the 21-month progress of Khan as Interior Minister. However, Khan was held responsible for failing to implement and enforce the proposals and plans of the National Action Plan. Khan was also criticised for delaying the inauguration of the Safe City Project in Islamabad, under which 1,800 surveillance cameras were installed across the city. During his tenure as Interior Minister, he issued the approval to launch Biometpric passport in Pakistan.

He ceased to hold ministerial office on 28 July 2017 when the federal cabinet was disbanded following the resignation of Sharif after the Panama Papers case decision. A day earlier, Khan had announced that he was considering stepping down as Interior Minister and resigning from membership in the National Assembly because of his differences with the party leaders. After the resignation of Sharif, Khan held a farewell meeting with his Interior Ministry staff and made it clear that he would not become part of the next federal cabinet of the incoming prime minister Shahid Khaqan Abbasi, who is junior to him. As of September 2017, Khan was the longest continuously-serving member of the National Assembly, who was elected to the National Assembly eight times since 1985 election. On 4 August 2017, Abbasi announced his cabinet without Khan being a member. However, reportedly Khan did not renounce his seat in the National Assembly. Khan was accused for giving safe passage to Pervez Musharraf for going out of Pakistan despite a treason case against him.

In February 2018, Imran Khan offered Khan to join Pakistan Tehreek-e-Insaf before 2018 general election. On 27 February, it was reported Nawaz Sharif has parted ways with Khan.

In June 2018, he parted ways with PML-N and announced to run for the 2018 general election as an independent candidate instead of seeking the nomination of PML-N and criticized Sharif brothers saying “These Sharifs will not able to show their faces anywhere if I decide to open my mouth.” In July 2018, he in a press conference said “My decision to run as an independent candidate does not mean I have parted ways with the PML-N”.

He was re-elected to the Provincial Assembly of the Punjab as an independent candidate from Constituency PP-10 (Rawalpindi-V) in the 2018 general election. In the same election, he also ran for the seat in the National Assembly as an independent candidate from Constituency NA-59 (Rawalpindi-III) and Constituency NA-63 (Rawalpindi-VII), but was unsuccessful. Following the election, he went outside Pakistan and did not take oath of the provincial assembly seat.

In January 2019, a petition was filed in the Lahore High Court against Khan which directed the Election Commission of Pakistan to de-notify him for his failure to take oath as member of the Punjab Assembly.