Rajagopalachari was born to Chakravarti Venkataryan, munsiff of Thorapalli Village and Chakravarti Singaramma on 10 December 1878 in Thorapalli, Madras Presidency. The couple already had two sons, Chakravarti Narasimhachari and Chakravarti Srinivasa.

A weak and sickly child, Rajagopalachari was a constant worry to his parents who feared that he might not live long. As a young child, he was admitted to a village school in Thorapalli then at the age of five moved with his family to Hosur where Rajagopalachari enrolled at Hosur R.V.Government Boys Hr sec School. He passed his matriculation examinations in 1891 and graduated in arts from Central College, Bangalore in 1894. Rajagopalachari also studied law at the Presidency College, Madras, from where he graduated in 1897.

Rajagopalachari married Alamelu Mangalamma in 1897 and the couple had five children; three sons—C. R. Narasimhan, C. R. Krishnaswamy, and C. R. Ramaswami—and two daughters—Lakshmi Gandhi née C. R. and Namagiri Ammal C. R. . Mangamma died in 1916 whereupon Rajagopalachari took sole responsibility for the care of his children. His son Chakravarthi Rajagopalachari Narasimhan was elected to the Lok Sabha from Krishnagiri in the 1952 and 1957 elections and served as a member of parliament for Krishnagiri from 1952 to 1962. He later wrote a biography of his father. Rajagopalachari's daughter Lakshmi married Devdas Gandhi, son of Mahatma Gandhi while his grandsons include biographer Rajmohan Gandhi, Philosopher Ramchandra Gandhi and former governor of West Bengal Gopalkrishna Gandhi.

Rajagopalachari's interest in public affairs and politics began when he commenced his legal practice in Salem in 1900. Inspired by Indian independence Activist Bal Gangadhar Tilak in the early 1900s, he later became a member of the Salem municipality in 1911. In 1917, Rajagopalachari was elected Chairman of the municipality and served from 1917 to 1919 during which time he was responsible for the election of the first Dalit member of the Salem municipality. Rajagopalachari joined the Indian National Congress and participated as a delegate in the 1906 Calcutta session and the 1907 Surat session. In 1917, he defended Indian independence Activist P. Varadarajulu Naidu against charges of sedition and two years later participated in the agitations against the Rowlatt Act. Rajagopalachari was a close friend of the founder of Swadeshi Steam Navigation Company V. O. Chidambaram Pillai as well as greatly admired by Indian independence Activists Annie Besant and C. Vijayaraghavachariar.

Rajagopalachari started the Tamil Scientific Terms Society in 1916, a group that coined new words in Tamil for terms connected to botany, chemistry, physics, astronomy and mathematics. At about the same time, he called for Tamil to be introduced as the medium of instruction in schools.

After Mahatma Gandhi joined the Indian independence movement in 1919, Rajagopalachari became one of his followers. He participated in the Non-Cooperation movement and gave up his law practice. In 1921, he was elected to the Congress Working Committee and served as the General Secretary of the party before making his first major breakthrough as a leader during the 1922 Indian National Congress session at Gaya when he strongly opposed collaboration with colonial administration and participation in the diarchial legislatures established by the Government of India Act 1919. While Gandhi was in prison, Rajagopalachari led the group of "No-Changers", individuals against contesting elections for the Imperial Legislative Council and other provincial legislative councils, in opposition to the "Pro-changers" who advocated council entry. When the motion was put to the vote, the "No-changers" won by 1,748 to 890 votes resulting in the resignation of important Congress Leaders including Pandit Motilal Nehru and C. R. Das, the President of the Indian National Congress. When the Indian National Congress split in 1923, Rajagopalachari was a member of the Civil Disobedience Enquiry Committee. He was also involved in the Vaikom Satyagraha movement against untouchability during 1924–25.

An accomplished Writer both in his mother tongue Tamil as well as English, Rajagopalachari was the founder of the Salem Literary Society and regularly participated in its meetings. In 1922, he published Siraiyil Tavam (Meditation in jail), a day-to-day account of his first imprisonment by the British from 21 December 1921 to 20 March 1922.

In the early 1930s, Rajagopalachari emerged as one of the major Leaders of the Tamil Nadu Congress. When Gandhi organised the Dandi march in 1930, Rajagopalachari broke the salt laws at Vedaranyam, near Nagapattinam, along with Indian independence Activist Sardar Vedaratnam and was afterwards imprisoned by the British. He was subsequently elected President of the Tamil Nadu Congress Committee. Following enactment of the Government of India Act in 1935, Rajagopalachari was instrumental in getting the Indian National Congress to participate in the 1937 general elections.

Regarded as a pioneer of social reform, Rajagopalachari issued temple entry proclamations in the Madras Presidency and worked towards the upliftment of Dalits. He played a pivotal role in the conclusion of the Poona Pact between B. R. Ambedkar and the Indian National Congress and spearheaded the Mahabal Temple Entry program in 1938. He was a staunch advocate of prohibition and was elected Secretary of the Prohibition League of India in 1930. On assuming the premiership of the Madras Presidency, he introduced prohibition throughout the province. where it remained in vogue until its removal by M. Karunanidhi over thirty years later. Rajagopalachari was also an active member of the All India Spinners Association. and a strong opponent of "linguistic states", which he felt would bring anarchy to India.

Rajagopalachari issued the Temple Entry Authorization and Indemnity Act 1939, under which restrictions were removed on Dalits and Shanars entering Hindu temples. In the same year, the Meenakshi temple at Madurai was also opened to the Dalits and Shanars. In March 1938 Rajagopalachari introduced the Agricultural Debt Relief Act, to ease the burden of debt on the province's peasant population.

Although his popularity at the regional level fluctuated greatly, it is believed that Rajagopalachari was able to exercise his stranglehold over provincial politics mainly because he was favoured by national Leaders such as Gandhi, Patel and Nehru. Critics feel that when the President of the Tamil Nadu Congress Committee K. Kamaraj and a majority of the provincial Leaders turned against him in the 1940s, Rajagopalachari clung on to a position of influence in regional politics through support from his colleagues at the centre.

Richard Casey, Governor of Bengal from 1944 to 1946, regarded Rajagopalachari as the wisest man in India. The best possible tribute to Rajagopalachari was from Mahatma Gandhi who referred to him as the "keeper of my conscience". Today, his private papers are part of the Archives at the Nehru Memorial Museum & Library, at Teen Murti House, Delhi.

Following the end of the war in 1945, elections followed in the Madras Presidency in 1946. During the last years of the war, Kamaraj was requested by Nehru, PM; Sardar Vallabbhai Patel, Home Minister; and Maulana Abul Kalam Azad to make Rajaji the Premier of Madras Presidency. Kamaraj, President of the Tamil Nadu Congress Committee, was forced to make [Tanguturi Prakasam] as Chief Ministerial candidate, by the elected members, to prevent Rajagopalachari from winning. However, Rajagopalachari did not contest the elections, and Prakasam was elected.

From 1946 to 1947, Rajagopalachari served as the Minister for Industry, Supply, Education and Finance in the Interim Government headed by Jawaharlal Nehru.

From 10 until 24 November 1947, Rajagopalachari served as Acting Governor-General of India in the absence of the Governor-General Lord Mountbatten, who was on leave in England to attend the marriage of Princess Elizabeth to Mountbatten's nephew Prince Philip. Rajagopalachari led a very simple life in the viceregal palace, washing his own clothes and polishing his own shoes. Impressed with his abilities, Mountbatten made Rajagopalachari his second choice to succeed him after Vallabhbhai Patel, when he was to leave India in June 1948. Rajagopalachari was eventually chosen as the governor-general when Nehru disagreed with Mountbatten's first choice, as did Patel himself. He was initially hesitant but accepted when Nehru wrote to him, "I hope you will not disappoint us. We want you to help us in many ways. The burden on some of us is more than we can carry." Rajagopalachari then served as Governor-General of India from June 1948 until 26 January 1950, and was not only the last Governor-General of India, but the only Indian national ever to hold the office.

By the end of 1949, an assumption was made that Rajagopalachari, already governor-general, would continue as President. Backed by Nehru, Rajagopalachari wanted to stand for the presidential election but later withdrew, due to the opposition of a section of the Indian National Congress mostly made up of North Indians who were concerned about Rajagopalachari's non-participation during the Quit India Movement.

On 26 January 1950, the Government of India adopted Hindi as the official language of the country, but because of objections in non-Hindi-speaking areas, it introduced a provision tentatively making English the second official language on a par with Hindi for a stipulated fifteen-year period to facilitate a switch to Hindi in non-Hindi speaking states. From 26 January 1965 onwards, Hindi was to become the sole official language of the Indian Union and people in non-Hindi speaking regions were compelled to learn Hindi. This led to vehement opposition and just before Republic Day, severe anti-Hindi protests broke out in Madras State. Rajagopalachari had earlier been sharply critical of the recommendations made by the Official Languages Commission in 1957. On 28 January 1956, Rajagopalachari signed a resolution along with Annadurai and Periyar endorsing the continuation of English as the official language. At an All-India Language Conference held on 8 March 1958, he declared: "Hindi is as much foreign to non-Hindi speaking people as English [is] to the protagonists of Hindi". When the Anti-Hindi agitations broke out in 1965, Rajagopalachari completely reversed his 1938 support for the introduction of Hindi and took a strongly anti-Hindi stand in support of the protests, On 17 January 1965, he convened the Madras state Anti-Hindi conference in Tiruchirapalli. angrily declaring that Part XVII of the Constitution of India which declared that Hindi was the official language should "be heaved and thrown into the Arabian Sea."

In 1951, he wrote an abridged retelling of the Mahabharata in English, followed by one of the Ramayana in 1957. Earlier, in 1961, he had translated Kambar's Tamil Ramayana into English. In 1965, he translated the Thirukkural into English and also wrote books on the Bhagavad Gita and the Upanishads in English as well as works on Socrates, and Marcus Aurelius in Tamil. Rajagopalachari often regarded his literary works as the best Service he had rendered to the people. In 1958, he was awarded the Sahitya Akademi Award for works in the Tamil language for his retelling of the Ramayana – Chakravarti Thirumagan. He was also one of the founders of the Bharatiya Vidya Bhavan, an organisation dedicated to the promotion of education and Indian culture. In 1959 the Bharatiya Vidya Bhavan published his book: "Hinduism: Doctrine and Way of Life".

On 31 May 1952, Rajagopalachari put an end to sugar rationing and followed up by abolishing control over food supplies on 5 June 1952. He also introduced measures to regulate the running of universities in the state. In 1953, he introduced a new education scheme known as the "Modified System of Elementary Education", which reduced schooling for elementary school students to three hours per day with students expected to learn the family vocation at home during the remainder of the day. The plan came in for sharp criticism and evoked strong protests from the Dravidian parties. The Dravida Munnetra Kazhagam dubbed the scheme Kula Kalvi Thittam or Hereditary Education Policy and attempted to organise massive demonstrations outside Rajagopalachari's house on 13 and 14 July 1953. The rising unpopularity of his government forced K. Kamaraj to withdraw his support for Rajagopalachari and on 26 March 1954, he resigned as President of the Madras Legislature Congress Party thereby precipitating new elections. During the subsequent poll held on 31 March 1954, Rajagopalachari fielded C. Subramaniam against Kamaraj. But Subramaniam could garner only 41 votes to Kamaraj's 93 and lost the elections. Rajagopalachari eventually resigned as Chief Minister on 13 April 1954, attributing the decision to poor health.

In 1954, during US Vice-President Richard Nixon's nineteen country Asian tour, he was lectured by Rajagopalachari on the consuming emotional quality of nuclear weapons. The pair discussed spiritual life, particularly reincarnation and predestination. Nixon wrote three pages of notes recording Rajagopalachari's words, claiming in his memoirs thirty-six years later that the afternoon "had such a dramatic effect on me that I used many of his thoughts in my speeches over the next several years."

While on a tour to the United States as a member of the Gandhi Peace Foundation delegation, in September 1962 Rajagopalachari visited American President John F. Kennedy at the White House. Rajagopalachari warned Kennedy of the dangers of embarking on an arms race, even one which the US could win. At the end of the meeting Kennedy remarked "This meeting had the most civilizing influence on me. Seldom have I heard a case presented with such precision, clarity and elegance of language". On 1 May 1955, Rajagopalachari appealed to the Government of India to cancel receipt of aid from America if the country continued with its nuclear tests.

Rajagopalachari tendered his official resignation from the Indian National Congress and along with a number of other dissidents organised the Congress Reform Committee (CRC) in January 1957. K. S. Venkatakrishna Reddiar was elected President and the party fielded candidates in 55 constituencies in the 1957 state assembly elections, to emerge as the second largest party in Madras state with 13 seats in the legislative assembly. The Congress Reform Committee also contested 12 Lok Sabha seats during the 1957 Indian elections. The committee became a fully-fledged political party and was renamed the Indian National Democratic Congress at a state conference held in Madurai on September 28–29, 1957.

On 4 June 1959, shortly after the Nagpur session of the Indian National Congress, Rajagopalachari, along with Murari Vaidya of the newly established Forum of Free Enterprise (FFE) and Minoo Masani, a classical liberal and critic of socialist Nehru, announced the formation of the new Swatantra Party at a meeting in Madras. Conceived by disgruntled heads of former princely states such as the Raja of Ramgarh, the Maharaja of Kalahandi and the Maharajadhiraja of Darbhanga, the party was conservative in character. Later, N. G. Ranga, K. M. Munshi, Field Marshal K. M. Cariappa and the Maharaja of Patiala joined the effort. Rajagopalachari, Masani and Ranga also tried but failed to involve Jayaprakash Narayan in the initiative.

Rajagopalachari was portrayed as an "archetypal" Tamil Brahmin "nemesis" of the anti-Brahmin demagogues constituting the self-proclaimed "Dravidian movement". A deeply religious, pious Hindu and follower of the Vedas and Upanishads, he was "accused" of being "pro-Sanskrit" and "pro-Hindi", positions that had in fact long been the consensus among other Dravidian-language speaking States in India who far exceeded Tamil speakers by population. Rajagopalachari found this "stigma" difficult to erase despite his vehement protests against the "imposition" of Hindi during the Madras Anti-Hindi agitations of 1965. He was also "accused" of attempting to heavily "Sanskritise" Tamil vocabulary through the inclusion of a large number of Sanskrit-derived words in his writings.

Apart from his literary works, Rajagopalachari also composed a devotional song Kurai Onrum Illai devoted to Lord Venkateshwara, a song set to music and a regular at Carnatic concerts. Rajagopalachari composed a benediction hymn sung by M. S. Subbulakshmi at the United Nations General Assembly in 1967.

In January 1971, a three-party anti-Congress coalition was established by the Congress (O), Jan Sangh and the Samyukta Socialist Party then on 8 January, the national executive of the Swatantra Party took the unanimous decision to join the coalition. The dissident parties formed an alliance called the National Democratic Front and fought against the Indian National Congress led by Indira Gandhi in the 1971 Indian general elections. However, the alliance fared badly. The Swatantra Party's tally was reduced to 8 seats from 23 in the 1967 elections. The decline of the Swatantra Party was also visible in the 1971 Tamil Nadu Legislative assembly elections in which it won just 19 seats down from 27 in the 1967 elections.

By November 1972, Rajagopalachari's health had begun to decline and on 17 December the same year, a week after his 94th birthday, he was admitted to the Government Hospital, Madras suffering from uraemia, dehydration and a urinary infection. In the hospital, he was visited by Chief Minister M. Karunanidhi, V. R. Nedunchezhiyan, V. V. Giri, Periyar and other state and national Leaders. Rajagopalachari's condition deteriorated in the following days as he frequently lost consciousness and he died at 5:44 pm on 25 December 1972 at the age of 94. His son, C. R. Narasimhan, was at his bedside at the time of his death reading him verses from a Hindu holy book.

Rajagopalachari was considered one of the most able statesmen in the national arena. Critics opine that he completely failed to gauge the thoughts and feelings of the masses – his introduction of Hindi and the Madras Scheme of Elementary Education have both been extensively criticised while his pacifist stance during the Quit India Movement and his "C. R. formula" angered the majority of his colleagues in the Indian National Congress. P. C. Alexander, a former governor of Tamil Nadu and Maharashtra, once wrote: