Due to climate change and intensive human activities, the frequency and severity of water-related disasters have increased and resulted in socio-economic and environmental damages. Assessment of water-related disaster risk is essential for risk mitigation and management for sustainable development. To investigate these issues, this study examined hazard, exposure, vulnerability, and resilience to disaster in the Yangtze River Economic Belt (YREB) of China, where water-related disasters have had an adverse impact on economic development and water resource security. We developed a multiple index system for the concerned YREB 131 cities, applied a risk assessment model to assess the spatio-temporal dynamics of the water-related disaster risk and identified the hotspots of risks in the YREB from 2000 to 2015 based on multisource observation data. The results showed that the average hazard, exposure, and vulnerability increased by 3.62%, 1.28%, and 2.07%, respectively, in the YREB during 2000–2015, revealing that water-related disaster risk presented an upward trend. The high-risk areas were mainly located in the middle and lower reaches of the YREB. The water-related disaster risk for the Chengdu-Chongqing City Cluster and urban agglomeration of the Yangtze River Delta increased and had spatial agglomeration characteristics. In addition, cities’ resilience can contribute to 14%–25% decreases in water-related disaster risk in the YREB. Thus, policy makers should focus more attention on water-related disaster risk reduction and improve cities’ resilience, especially in the middle and lower reaches of the YREB.