This study achieved the construction of earthquake disaster scenarios based on physics-based methods—from fault dynamic rupture to seismic wave propagation—and then population and economic loss estimations. The physics-based dynamic rupture and strong ground motion simulations can fully consider the three-dimensional complexity of physical parameters such as fault geometry, stress field, rock properties, and terrain. Quantitative analysis of multiple seismic disaster scenarios along the Qujiang Fault in western Yunnan Province in southwestern China based on different nucleation locations was achieved. The results indicate that the northwestern segment of the Qujiang Fault is expected to experience significantly higher levels of damage compared to the southeastern segment. Additionally, there are significant variations in human losses, even though the economic losses are similar across different scenarios. Dali Bai Autonomous Prefecture, Chuxiong Yi Autonomous Prefecture, Yuxi City, Honghe Hani and Yi Autonomous Prefecture, and Wenshan Zhuang and Miao Autonomous Prefecture were identified as at medium to high seismic risks, with Yuxi and Honghe being particularly vulnerable. Implementing targeted earthquake prevention measures in Yuxi and Honghe will significantly mitigate the potential risks posed by the Qujiang Fault. Notably, although the fault is within Yuxi, Honghe is likely to suffer the most severe damage. These findings emphasize the importance of considering rupture directivity and its influence on ground motion distribution when assessing seismic risk.