He has been a chairman/CEO of several Pan-African non-governmental organizations, CEO of a church, and has held senior positions in banking and financial services.

[5] Ekow Spio-Garbrah's early business experience included working as a mortgage banker in New Jersey, as a sales executive with Southwestern Bell, and as chairman of the Middle East Africa Group within the international public relations firm of Hill and Knowlton in New York.

In that capacity, from 1979 to 1985, he provided investment, export and tourism promotion counsel to the governments of Indonesia, Turkey, the Netherlands and Austria; financial relations advice to the Hong Kong and Shanghai Bank, Crédit Agricole of France, UBAF-Arab American Bank, and energy sector intelligence to OPEC.

As a Minister of Communication of Ghana, from 1997 to 1998,[9] Spio-Garbrah initiated, developed and implemented policies and programmes that supported the increasing convergence of telecommunications, broadcasting, the internet, publishing, news media and postal services, all of which were under his supervision.

Concurrently, as chairman of the National Communication Authority (NCA), he had responsibility for regulating all aspects of the telecom, Internet and broadcasting sectors.

Ekwow Spio-Garbrah was also in charge of the Public Education Committee which successfully re-introduced the VAT to Ghana after a disastrous first attempt in the early 1990s had left several protesters dead.

The GETFund law has been widely praised as one of the most transformative pieces of legislation in Africa relating to the education sector.

He was responsible for all aspects of strategic planning for the academic programmes, financial and accounting policies, and human resources and administrative systems for the operations of the private Christian University.

[17] In December 2006, Spio-Garbrah contested the leadership of Ghana's main opposition party, the National Democratic Congress (NDC).