She is a leading chartered accountant and co-founder in 1994 of Transparency International, former Vice President of the World Bank’s Africa Region Program. She has held several key positions within the Nigerian government including (from 2002) senior special assistant to the President of Nigeria on budget monitoring and price intelligence, where she led the institutional reform of the country's Public Procurement system through the establishment of the Due Process system in public contracting. She was a member of the 12-person Economic Team of President Olusegun Obasanjo (2003-07) and in this capacity, negotiated the OECD G-8 anticorruption Transparency Compact with Nigeria which was announced at the 2004 G-8 Sea Island Summit in the United States.

As Minister of Solid Minerals Development (from 2005) she reformed Nigeria's mining sector to internationally recognized standards especially through her work on a new Minerals Act, a world class and autonomous Nigeria Geological Survey Agency. Ezekwesili served as the pioneer Chairperson for the Nigeria Extractive Industries Transparency Initiative (NEITI, 2004-07) and led the voluntary sign-on of Nigeria to the global EITI Principles. She supervised the first ever publicly disclosed physical, financial and process audits of the oil and gas sector. As Minister of Education (from June 2006) she led an extensive and comprehensive reform program, and her blueprint for overhauling the sector is a reference document from which other countries in Africa have borrowed ideas. In 2012, she became a senior advisor on Africa Economic Development Policy at the Open Society Foundations in New York, assisting the Mano River governments with economic policy reforms.

Following the abduction of 219 girls from their secondary school in Chibok in 2014, Dr Ezekwesili co-convened the viral ‘#BringBackOurGirls’ campaign on social media, which trended internationally and has world-wide support from international personalities including the former First Lady, Michelle Obama.
Through sustained advocacy of the #BringBackOurGirls, freedom was secured for 107 of the abducted girls and the Movement continues to advocate for the remaining 112 ChibokGirls. She sits on numerous board and has received many awards.