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Few conservation studies have examined fish communities in entire drainage basins, especially in developing regions such as Southeast Asia, one of the most diverse biomes globally. The aim of this study was to establish conservation projections for the whole of the Irrawaddy River system, based on fish diversity patterns, human impact, and environmental change.The Irrawaddy River is one of the five largest rivers in Southeast Asia. Although it has very high diversity of fish species and species endemism, our understanding of resident fish status remains poor.Based on 1,726 field survey and 1,056 database records, 470 fish species and their distribution patterns (i.e. alpha, beta, threatened species, and endemic species diversities) in sub‐basins of the Irrawaddy drainage were identified. Canonical correspondence analysis of diversity and environmental patterns indicated that climatic factors had the largest effect on diversity, compatible with the species–energy theory.Fish conservation priorities of sub‐basins were evaluated based on diversity patterns and human impact. The delta and Manipur basin regions were highlighted as areas of focus for future fish diversity conservation, and the importance of connectivity in the Irrawaddy main stem was demonstrated.The results of this study will be valuable for future management of the Irrawaddy basin and as a reference for other river basins when implementing protection strategies for fish diversity. This study also advocates the need for systematic investigations across entire drainage basins and further detailed studies on the ecological conditions of poorly studied river systems. [ABSTRACT FROM AUTHOR]