Ramachandran made his film debut in 1936, in the film Sathi Leelavathi, directed by Ellis Dungan, an American-born film Director. Generally starring in romance or action films, MGR got his big breakthrough in the 1950 film Manthiri Kumari, written by M. Karunanidhi. Soon he rose to popularity with the 1954 film Malaikkallan. He acted as hero in the Tamil film industry's first ever Gevacolor movie, the 1955 Alibabavum 40 Thirudargalum. He rose to become the heartthrob of millions of Tamilians with movies such as Thirudadhe, Enga Veettu Pillai, Aayirathil Oruvan, Anbe Vaa, Mahadevi, Panam Padaithavan, Ulagam Sutrum Vaalibhan, etc. He won the National Film Award for Best Actor for the film Rickshawkaran in 1972. He acted in many movies that appealed to the direct sentiments of the Common man and the rich as well. His 1973 blockbuster Ulagam Sutrum Vaalibhan broke the previous box office records of his movies. It was one of the few movies filmed abroad in those days. It was shot in Singapore, Malaysia, Thailand, Hong Kong and Japan. The DMK tried very hard to illegally prevent the screening of the film using strong-arm tactics, but ultimately failed in its attempt. His acting career ended in 1987 with his last film Ullagam Suthi Paru, in which he acted even though he had been diagnosed with kidney failure.

MGR was a member of the Congress Party till 1953, and he used to wear khādī. In 1953 MGR joined the Dravida Munnetra Kazhagam (DMK) attracted by founder C.N. Annadurai. He became a vocal Tamil and Dravidian nationalist and prominent member of the DMK ("Dravida Munnetra Kazhagam" aka Dravidian Progressive Federation). He added glamour to the Dravidian movement which was sweeping Tamil Nadu. MGR became a member of the state Legislative Council in 1962. At the age of 50, he was first elected to the Tamil Nadu Legislative Assembly in 1967. After the death of his mentor, Annadurai, MGR became the treasurer of DMK in 1969 after Muthuvel Karunanidhi became the Chief Minister.

He personally offered relief in disasters and calamities like fire, flood, drought, and cyclones. He was the first donor during the war with China in 1962 (Sino-Indian War), donating Rs. 75,000 to the war fund. He was the founder and Editor of Thai weekly magazine and Anna daily newspaper in Tamil. He was the owner of Sathya Studios and Emgeeyar Pictures (willed to charity) which produced many of the films he acted in. He had gifted a golden sword weighing half a Kilogram to Mookambika temple in Kollur, Udupi district.

M.G.R's first marriage was to Chitarikulam Bargavi, also known as Thangamani, who died early due to an illness. He later married for the second time, to Satyanandavati, who also died soon after marriage due to tuberculosis. In 1965, M.G.R. married for the third time, this time to V. N. Janaki a former Tamil film Actress. Janaki divorced her husband, Ganapathy, to marry M.G.R.

The actor and Politician M. R. Radha and MGR had worked in 25 films together. On 12 January 1967, Radha and a Producer visited MGR to talk about a Future film project. During the conversation, M. R. Radha stood up and shot MGR in his left ear twice and then tried to shoot himself.

Upon his ouster from DMK, Ramachandran floated a new party which he called Anna Dravida Munnetra Kazhagam (ADMK), later renamed All India Anna Dravida Munnetra Kazhagam (AIADMK), the only powerful opponent of the DMK. He mobilized between 1972 and 1977 to spread and preach his party ambition with films like Netru Indru Naalai (1974), Idhayakani (1975), Indru Pol Endrum Vazhga (1977), etc.

Anna Dravida Munnetra Kazhagam allied with Indian National Congress (Indira) in the 1977 parliamentary election. However, when Janata Party won the election and Morarji Desai became the Prime Minister, M. G. Ramachandran extended unconditional support to the Janata party Government. He continued his support to the Charan Singh Government in 1979. After the fall of the Charan Singh government, fresh parliamentary elections were conducted in 1980. Dravida Munnetra Kazhagam struck alliance with INC(I). ADMK and Janata Party alliance won only 2 seats in Tamil Nadu in that parliamentary election. INC(I) won the election and Indira Gandhi became the Prime Minister. Congress-DMK victory in the 1980 parliamentary election emboldened their alliance and made them think that people lost their faith in M. G. Ramachandran government. DMK pressed the central government to dismiss the Tamil Nadu government using similar allegations used by MGR to dismiss DMK government in 1976. The ADMK ministry and the assembly were dismissed by the central government and fresh elections conducted in 1980. Despite their victory at the 1980 Lok Sabha polls, DMK and Indira Congress failed to win the legislative assembly election. ADMK won the election and its leader and incumbent Chief Minister, M. G. Ramachandran was sworn in as Chief Minister for the second time. He became the first leader since K. Kamaraj to win a re-election as Chief Minister.

Other criticisms have been on MGR's centralised decision-making, which many blame for inefficiency and corruption taking hold of his administration. Some examples stated by the critics include Goondas act in 1982 and other acts that limited political criticism in the media, which led to a "police state" during his administration. While these criticisms have been in the minority, supporters of MGR counter that most of these problems were a result of the party members serving MGR rather than the leader himself. While he is not considered a divisive figure in the state, critics and supporters alike agree that his charisma and popularity trumped policy decisions that led to his eventual success during his tenure as chief minister.

After the operation, MGR's voice changed. Since he had been shot in his ear, MGR lost hearing in his left ear and had ringing in the ear problems. These further surfaced in 1983 when he had kidney problems. When Sinnappa Devar paid his first visit to see MGR at the hospital after the shooting incident he paid MGR an advance for MGR's next movie. After getting released from the hospital and finishing Arasakattalai, MGR acted in Devar's movie Vivasaayee against doctors' advice. Due to the operation, MGR's speaking parts in the movie Kaavalkaaran were reduced. This was the only movie in which MGR spoke with old and new voices between scenes: MGR was acting in the film Kaavalkaran in 1967 opposite J. Jayalalithaa when the shooting occurred.

Indira Gandhi was assassinated on 31 October 1984. During the same time, M. G. Ramachandran was diagnosed with kidney failure and admitted into a hospital in New York City. Rajiv Gandhi assumed office immediately and this required a fresh mandate from the people. Indian National Congress (Indira) and Anna Dravida Munnetra Kazhagam formed an alliance and contested the election. M. G. Ramachandran was confined to the hospital. Video coverage of MGR recuperating in hospital along with Indira Gandhi's assassination were stitched together by the ADMK man in charge of campaigning, R. M. Veerappan. The video was distributed and played across all over Tamil Nadu. Rajiv Gandhi visited cyclone-hit areas in Tamil Nadu, which also boosted the alliance. The sympathy wave created by Indira's assassination, MGR's illness and Rajiv Gandhi's charisma helped the alliance sweep the election.[1][2] DMK leader M. Karunanidhi did not contest this election, due to the fact that the ADMK leader M.G.R was admitted to a hospital in the U.S. and Indira Gandhi being assassinated. It was a landslide victory for AIADMK-Congress combine which won 195 seats in assembly polls. The electoral victory proved the undying charisma of MGR upon the masses.

In October 1984, MGR was diagnosed with kidney failure, which was further complicated by diabetes, a mild heart attack and a massive stroke. He was rushed to the Downstate Medical Center, Brooklyn, United States for treatment, undergoing a kidney transplant. He returned to Chennai on 4 February 1985. He was sworn in as chief minister of Tamil Nadu for the third consecutive term on 10 February 1985. The next 2 years and 10 months were spent in frequent trips to the United States for treatment.

MGR never fully recovered from his illness and died on 24 December 1987 at 3:30 am in his Ramavaram Gardens residence in Manapakkam after his prolonged illness. He was almost 71. His death sparked off a frenzy of looting and rioting all over the state. Shops, cinemas, buses and other public and private property became the target of violence let loose. The police had to resort issuing shoot-at-sight orders. Schools and colleges immediately announced the holidays till the situation came in control. The violence during the funeral alone left 29 people dead and 47 police personnel badly wounded.

This state of affairs continued for almost a month across Tamil Nadu. Around one million people followed his remains, around 30 followers committed suicide and people had their heads tonsured. After his death, his political party, the All India Anna Dravida Munnetra Kazhagam, split between his wife Janaki Ramachandran and J. Jayalalithaa; they merged in 1988.

In 1989 Dr. M. G. R. Home and Higher Secondary School for the Speech and Hearing Impaired was established at the erstwhile residence MGR Gardens, Ramavaram, in accordance with his last will & testament written in January 1987. His official residence at 27, Arcot Street, T. Nagar is now M.G.R. Memorial House and is open for public viewing. His film studio, Sathya Studios, has been converted into a women's college.

M.G.R's autobiography "Naan Yaen Piranthaen" (Why I was born) was published in 2003 in two volumes.

Karunanidhi claimed on 1 April 2009 and again on 13 May 2012 that MGR was ready for the merger of his party with the DMK in 1979, with Biju Patnaik acting as the mediator. The plan failed, because Panruti Ramachandran, who was close to MGR acted as a spoiler and MGR changed his mind.

Once he became Chief Minister of Tamil Nadu, he placed great emphasis on social development, especially education. One of his most successful policies was the conversion of the "Midday Meal Scheme", introduced by the popular Congress Chief Minister and kingmaker K Kamaraj, which already was encouraging underprivileged children to attend school, into "MGR's Nutritious Meal Scheme" in the government-run and -aided schools in Tamil Nadu by adding saththurundai – a nutritious sugary flour dumpling. This scheme was at a cost of Rs. 1 billion and was imposed in 1982. A little more than 120,000 children of the state were benefited. He also introduced Women's Special buses. He introduced a liquor ban in the state and preservation of old temples and historical monuments, ultimately increasing the state's tourist income. He set up a free school for the cinema technicians children in Kodambakkam called MGR Primary & Higher Secondary School which provided free mid-day meals in the 1950s. He led the ADMK to victory in the 1984 assembly elections, despite not taking part in the campaigning. At that time he was undergoing medical treatment in America and his images were broadcast in Tamil Nadu through cinema halls. This was an effective campaign tactic and ADMK won the elections claiming around 56% of assembly seats, indicating the depth of his popular support. He won his seat in a double landslide victory in 1984. He still holds the record of being the chief minister with the highest consistent longevity of more than a decade.

To commemorate MGR's Birth centenary in 2017, the Ministry of Finance, Government of India decided to issue ₹100 and ₹5 coins that would bear his image as a portrait along with an inscription of "DR. M. G. Ramachandran Birth Centenary".