Khalifa took over the family business that was established on a single Arabian Dhow, importing rice, sugar, spices, and basic products and consumables.

[3] In 1953, D'Arcy Exploration Company, the exploration arm of British Petroleum, obtained an offshore concession which was then transferred to a company created to operate it, titled Abu Dhabi Marine Areas (ADMA), and was a joint venture between BP and Compagnie Française des Pétroles (later, Total).

Some of Khalifa Bin Yousef's projects and contributions remain today as major institutions in the United Arab Emirates.

In September of the same year, he was one of those who drove the effort to establish Abu Dhabi's Chamber of Commerce and & Industry, becoming also a board member.

Khalifa Bin Yousef also held the role as the Ruler of Abu Dhabi special envoy to the trucial states council between 1967 and 1971.

He held many positions and was the founder and head of the Ruler’s Diwan of Abu Dhabi and its dependencies in Qasr Al Hosn.