Kesri became politically active at the age of 13, with his involvement in the Indian independence movement. Kesri was arrested for his political activities several times between 1930 and 1942. He was elected president of st of Constituencies of the Lok Sabha|Lok Sabha Constituency]] in 1967 where he won on a Janata Party ticket after being given a late call by the then-BJP President S.N. Sinha. He represented Bihar in the Rajya Sabha for five terms between July 1971 and April 2000, being reelected on April 1974, July 1980, April 1988, and April 1994. He was Union Minister during the regimes of Indira Gandhi, Rajiv Gandhi and P.V. Narasimha Rao as Prime Minister of India.
Kesri served as treasurer of the Congress party for more than a decade. In addition, he was elected unanimously as President of the Congress Parliamentary Party on 3 January 1997. After P.V. Narasimha Rao stepped down as president of the Congress in September 1996, Kesri was appointed as the new president of the party.
The following years were difficult for the Congress Party. Kesri's lack of popular support among the masses caused further damage to the party. Kesri's most controversial act was the sudden withdrawal of support to H.D. Deva Gowda's United Front government, which led to the fall of the government in April 1997. However, a compromise was reached and the United Front elected I.K. Gujral as the subsequent new leader with continued support from the Congress party.
In the first week of November 1997, part of the Jain Commission's report inquiring into the conspiracy angle of the assassination of Rajiv Gandhi was leaked to the press. It was reported that the Jain Commission had indicted Dravida Munnetra Kazhagam (DMK) for its ties with the LTTE, the organization involved in the assassination of Gandhi. The DMK was one of the constituents of the United Front that was in power at the center. Moreover the party had three ministers on the council of ministers headed by Prime Minister Gujral. The Congress demanded removal from the government the ministers belonging to the DMK. Between 20 and 28 November 1997, an exchange of letters took place between Kesri and Prime Minister Gujral; however, the prime minister refused to meet the demands of the Congress. Finally, on 28 November 1997, Congress withdrew its support for the Gujral government. When no alternative government could be formed, the Lok Sabha was dissolved, paving the way for midterm elections.
The Congress did not adequately prepare for the midterm elections. A number of senior leaders of the party, such as Rangarajan Kumaramangalam, Aslam Sherkhan, and other leaders, openly expressed displeasure with Kesri's leadership and left the party. After Sonia Gandhi decided to campaign for the party, she replaced Kesri as the main party campaigner. Sonia attracted huge crowds in her campaign rallies but did not win the election for the party. Nevertheless, the Congress did maintain a respectable tally of 140 seats. During the election campaign, there were a series of bomb blasts in Coimbatore, where BJP President L.K. Advani was scheduled to address an election rally. About 50 people were killed in the blasts. After the blasts, Kesri made a statement that the bomb blasts were the handiwork of the RSS (Rashtriya Swayamsevak Sangh), and moreover, he had the proof of RSS involvement in the blasts. The RSS sued Kesri for defamation, but Kesri was granted bail by a city court in 1998
After the electoral defeat, Kesri was stripped of his post in March 1998 by the Congress Working Committee. Sonia Gandhi was appointed president of the Congress party in his place. Kesari's removal from the Congress Working Committee is considered by some as a betrayal of the party constitution, considering how Pranab Mukherjee and others conspired to eliminate Kesri from the party for Sonia Gandhi.
Kesri, along with other members of the Working Committee including Tariq Anwar, was "roughed up" at Congress Party headquarters on 19 May 1999 by what has been described as an "angry mob" and "Congress goons", following the split in the Congress that led to the formation of the Nationalist Congress Party. After his exit from office, he maintained a relatively low profile in politics. He was also denied party candidature for the Rajya Sabha once his last term ended in April 2000.