Abstract: The recent growth of agriculture, industry and urban areas in Vietnam requires a large amount of water consumption as a production factor. This paper explores the water resource use efficiency (WRUE) of the Vietnamese Dong Nai River Basin during 2010–2017. Twenty-nine sub-basins of the Dong Nai River Basin are selected as decision-making units to characterize WRUE. The relationship between water use and the socio-economic development is analyzed using the WRUE in the social and economic subsystems. The results show that: (1) most water is used by agriculture (72% of water resource consumption), next to industry (12%) and service (9%); (2) On the WRUE in both social and economic subsystems, Phuoc Hoa and Sai Gon sub-basins have the efficiency optimum. Water use in Can Don is technically efficient. Sub-basins of Dong Nai 1–8 have the lowest technical efficiency; (3) The Dong Nai River Basin has a positive change in total factor productivity over time, however WRUE decreases gradually; and (4) Urban areas use less water than the rural areas. An improvement of the WRUE is an essential way for sustaining water uses in the severe water shortage sub-basins such as Phuoc Hoa, Sai Gon, and Can Don. The study findings imply that two-stage DEA is useful for policymakers to make right decisions for water resource management and the improvement of WRUE.