Indira Gandhi introduced Pranab Mukherjee to the world of politics after he successfully managed the Midnapore by-election campaign of independent candidate, V K Krishna Menon. In July 1969, he became a member of the Rajya Sabha, and was re-elected to the House in 1975, 1981, 1993 and 1999.

A year after Indira Gandhi’s assassination in 1984, when Rajiv Gandhi took over the reins of the Congress, Mukherjee felt sidelined and parted ways with the party to form his own political outfit in West Bengal. However, Mukherjee and Rajiv Gandhi reconciled soon enough and the Bengal politician returned to the Congress. After Rajiv's assassination in 1991, Mukherjee was seen as a potential prime minister, but P V Narasimha Rao took the post.

Mukherjee, also regarded as the architect of Sonia Gandhi's entry into politics, was made General Secretary of the All India Congress Committee in 1998-99. In 2000, he was appointed the president of the Congress' West Bengal unit — a post he went on to hold until his resignation in 2010.

As defence minister and then foreign minister, his tenure coincided with the warming of relations between the United States and India; as finance minister, he managed India’s response to the 2008 global financial crisis. While India apparently recovered swiftly from the crisis, it is in this period that it became clear that Mukherjee — once called Indira Gandhi’s “man for all seasons” — was perhaps in fact lost in time.

On July 25, 2012, Mukherjee was sworn in as the thirteenth President of India. He was the first Bengali to hold the top post. As President, Mukherjee promulgated Criminal Law (Amendment) Ordinance, 2013, which provides for amendment of the Indian Penal Code, Indian Evidence Act, and Code of Criminal Procedure, 1973, on laws related to sexual offences. Mukherjee rejected at least 24 mercy pleas, including that of convicted terrorists Yakub Memon, Ajmal Kasab and Afzal Guru. In January 2017, Mukherjee said he would not contest the 2017 Presidential elections owing to failing health. He was awarded India's highest civilian honour, the Bharat Ratna, in 2019.