[14] Neil O'Brien worked in publishing and retired as the chairman and managing director of Oxford University Press India as well as leading the Anglo-Indian community for two decades.

In 1991, he finally quit Ogilvy and set up his own knowledge, education and publishing company, Big Ideas – since renamed Derek O'Brien and Associates.

[21][22][23][24][25][26] Derek O'Brien has conducted quizzes in the UAE (Dubai and Abu Dhabi), Bahrain, Kuwait, Qatar, Oman, Singapore, Sri Lanka, Bangladesh and the United States.

[39] He later wrote that he was drawn to the charisma and personality of the Trinamool Congress leader (now chief minister of Bengal) Mamata Banerjee, and felt she was the only one who could defeat the then CPI(M)-led government in the state.

[40][41] O'Brien soon became a spokesperson for the Trinamool Congress and was identified as the rare white-collar, English-speaking politician in the party.

[43][44] O'Brien is frequently seen on news television shows and is a regular commentator on political and policy issues.

In 2011, following the Trinamool Congress victory in the West Bengal assembly election, O'Brien was sent to the Rajya Sabha.

[74][75] Ministry of Parliamentary Affairs sought his suspension, along with some other members, as a consequence for his actions under rule 256 of procedure and conduct of business.

[76] He was suspended once again on 21 December 2021 for allegations of throwing a rulebook, as he was protesting against the Elections Law (Amendment) Bill, 2021.

[76] On 14 December 2023 he was suspended again from the Rajya Sabha following a confrontation with the Chairman, Jagdeep Dhankhar[10] He is a member of the Parliamentary Standing Committee on Home Affairs.

[77] On 6 January 2022 he wrote to Anand Sharma, head of the committee, to discuss the alleged app "Tek Fog" that "has serious ramifications and could jeopardise national security.".