[9][10] His father worked as a general manager of Mysore and Minerva Mills and subscribed to Fabian Socialist ideals that influenced Nilekani in his early years.

Nilekani became the chief executive officer of Infosys in March 2002 and served as CEO of the company through April 2007, when he relinquished his position to his colleague Kris Gopalakrishnan and became co-chairman of the board of directors.

Nilekani left Infosys in July 2009 to serve as the chairman of the Unique Identification Authority of India, a cabinet-ranking position that he entered under the invitation of Prime Minister Dr. Manmohan Singh.

This initiative aims to provide a unique identification number for all residents of India and will be used primarily as the basis for the efficient delivery of welfare services.

[14] The identification method will be biometric, and the drive to create this government database of the entire population of India has been called "the biggest social project on the planet.

In 2016, World Bank Chief Economist Paul Romer called Aadhaar “the most sophisticated ID programme in the world.” This program is criticized for violating people's privacy and exposing personal information.

[20] Nilekani joined Indian National Congress in March 2014 and contested from the Bangalore South constituency where he lost by 228,575 votes[21] to BJP candidate Ananth Kumar in the 2014 Lok Sabha election.

[26] Set up by the Nilekanis with an initial commitment of $10 million (about Rs 82 crore), EkStep looks at solving the 'learning problem' by creating a technology-led platform to help children in improving their 'learning outcomes' quite early in their life.

NCAER is among a handful of think tanks globally that collect primary survey data on a scientific, national basis covering households, enterprises, consumers, and individuals.

Nilekani is also a serial investor and he has invested in technologoy startups including 10i Commerce, Juggernaut, Mubble Networks, Fortigo, P2SME, Railyatri, Axiom Consulting, Systemantics India, Sedemac Mechatronics, Disha Medical Services, Tracxn Technologies, and LetsVenture.