Both energy production and consumption can simultaneously affect regional air quality, local water stress and the global climate. Identifying the air quality–carbon–water interactions due to both energy sources and end-uses is important for capturing potential co-benefits while avoiding unintended consequences when designing sustainable energy transition pathways. Here, we examine the air quality–carbon–water interdependencies of China’s six major natural gas sources and three end-use gasfor-coal substitution strategies in 2020. We find that replacing coal with gas sources other than coal-based synthetic natural gas (SNG) generally offers national air quality–carbon–water co-benefits. However, SNG achieves air quality benefits while increasing carbon emissions and water demand, particularly in regions that already suffer from high per capita carbon emissions and severe water scarcity. Depending on end-uses, non-SNG gas-for-coal substitution results in enormous variations in air quality, carbon and water improvements, with notable air quality–carbon synergies but air quality–water trade-offs. This indicates that more attention is needed to determine in which end-uses natural gas should be deployed to achieve the desired environmental improvements. Assessing air quality–carbon–water impacts across local, regional and global administrative levels is crucial for designing and balancing the co-benefits of sustainable energy development and deployment policies at all scales.