Nehru became a barrister and settled in the city of Allahabad, Uttar Pradesh. Many of Motilal's suits involved civil cases and soon he made a mark for himself in the legal profession of Allahabad. With the success of his practice, he bought a large family home in the Civil Lines of the city and aptly named the house Anand Bhavan (lit. Abode of happiness). In 1909 he reached the pinnacle of his legal career by gaining the approval to appear in the Privy Council of Great Britain. His frequent visits to Europe, angered the Kashmiri Brahmin community as he refused to perform the traditional "prayashchit" or reformation ceremony after crossing the ocean (according to Orthodox Hinduism, one lost his caste after crossing the ocean, and was required to perform certain rites to regain caste).

Nehru was a man of many elitist habits and had a westernized lifestyle. He was one of the moderate, wealthy leaders of the Indian National Congress. Under the influence of Mahatma Gandhi in 1918, Nehru became one of the first to transform his life to exclude western clothes and material goods, adopting a more native Indian lifestyle. To meet the expenses of his large family and large family homes (he built Swaraj Bhavan later), Nehru had to occasionally return to his practice of law.

Motilal Nehru twice served as President of the Congress Party. He was arrested during the Non-Cooperation Movement. Although initially close to Gandhi, he openly criticized Gandhi's suspension of civil resistance in 1922 due to the murder of policemen by a riotous mob in Chauri Chaura in Uttar Pradesh. Motilal joined the Swaraj Party, which sought to enter the British-sponsored councils.

In 1923, Nehru was elected to the new Central Legislative Assembly of British India in New Delhi and became leader of the Opposition. In that role, he was able to secure the defeat, or at least the delay, of Finance bills and other legislation. He agreed to join a Committee with the object of promoting the recruitment of Indian officers into the Indian Army, but this decision contributed to others going further and joining the Government itself.

In March 1926, Nehru demanded a representative conference to draft a constitution conferring full Dominion status on India, to be and enacted by the parliament. This demand was rejected by the Assembly, and as a result Nehru and his colleagues left the Assembly and returned to the Congress.

The entry of Motilal's glamorous, highly-educated son Jawaharlal Nehru into politics in 1916, started the most powerful and influential Indian political dynasty. When in 1929, Motilal Nehru handed over the Congress presidency to Jawaharlal (Jawaharlal was elected, with Gandhi's backing), it greatly pleased Motilal and Nehru family admirers to see the son take over from his father. Jawaharlal had opposed his father's preference for dominion status, and had not left the Congress Party when Motilal helped found the Swaraj Party.

Motilal Nehru chaired the famous Nehru Commission in 1928, that was a counter to the all-British Simon Commission. Nehru's Report, the first constitution written by Indians only, conceived a dominion status for India within the Empire, akin to Australia, New Zealand and Canada. It was endorsed by the Congress Party, but rejected by more radical Indians who sought complete independence, and by many Muslims who didn't feel their interests, concerns and rights were properly represented.
Motilal Nehru married Swaroop Rani, a Kashmiri Brahmin.

Motilal Nehru's age and declining health kept him out of the historic events of 1929 - 1931, when the Congress adopted complete independence as its goal and when Gandhi launched the Salt Satyagraha. He was arrested in 1930, however, after his son was arrested, but was soon released due to his failing health. He died on 6 February 1931.

Motilal Nehru is largely remembered for being the patriarch of India's most powerful political dynasty which has since produced three Prime Ministers. The widow of Nehru's great-grandson Rajiv Gandhi, Mrs. Sonia Gandhi leads the current Congress coalition government in India. Her son Rahul Gandhi is a powerful Member of Parliament and General Secretary of the Congress Party. Also the widow of another great-grandson Sanjay Gandhi, Mrs Maneka Gandhi as well as her son Varun Gandhi are member's of India's Parliament representing the main opposition party, the Bharatiya Janata Party (BJP).