The sustainable development of the hydropower megaproject (HM) is one of the critical components of sustainable water resources management. Hence, an accurate assessment of the impacts of social-economic-ecological losses (SEEL) on the sustainability of the HM system is of utmost importance. This study proposes an emergy-based sustainability evaluation model incorporating the social-economic-ecological losses (ESM-SEEL), which integrated the inputs and outputs during HM's construction and operation into an emergy calculation account. The Three Gorges Project (TGP) on the Yangtze River is selected as a case study to comprehensively evaluate the HM's sustainability from 1993 to 2020. Subsequently, the emergy-based indicators of TGP are compared with several hydropower projects in China and worldwide to analyze the multi-impacts of hydropower development. The results showed that the river chemical potential (2.35 E+24sej) and the emergy losses (L) (1.39 E+24sej) are the primary emergy inflow sections (U) of the TGP system, accounting for 51.1% and 30.4% of the U, respectively. The flood control function of the TGP produced tremendous socio-economic benefits (1.24 E+24sej), accounting for 37.8% of the total emergy yield. The resettlement and compensation, water pollution during operation, fish biodiversity loss, and sediment deposition are the main L of the TGP, accounting for 77.8%, 8.4%, 5.6%, and 2.6%, respectively. Based on the enhanced emergy-based indicators, the assessment reveals that the sustainability level of the TGP falls in the middle range compared to other hydropower projects. Thus, along with maximizing the benefits of the HM system, it is necessary to minimize the SEEL of the HM system, which is a critical approach to promote the coordinated development of the hydropower and ecological environment in the Yangtze River basin. This study helps to understand the complex relationship between human and water systems and provides a novel framework that can be used as an evaluation index and insights for hydropower sustainability assessment.