The Yangtze River (YZR) regions have experienced rapid changes after opening up to economic reforms, and human activities have changed the land cover, ecology, and wildlife habitat quality. However, the specific ways in which those influencing factors changed the habitat quality during different periods remain unknown. This study assessed the wildlife habitat quality of the middle and lower YZR in the past (1980–2018) and in future scenarios (2050, 2100). We analyzed the relationships between habitat quality and various topological social-economic factors, and then mapped and evaluated the changes in habitat quality by using the Integrated Valuation of Environmental Services and Tradeoffs (InVEST) model. The results show that the slope (R = 0.502, P < 0.01, in 2015), elevation (R = 0.003, P < 0.05, in 2015), population density (R = –0.299, P < 0.01, in 2015), and NDVI (R = 0.366, P < 0.01, in 2015) in the study area were significantly correlated with habitat quality from 2000 to 2015. During the period of 1980–2018, 61.93% of the study area experienced habitat degradation and 38.07% of the study area had improved habitat quality. In the future, the habitat quality of the study area will decline under either the A2 scenario (high level of population density, low environmental technology input, and high traditional energy cost) or the B2 scenario (medium level of population density, medium green technology and lack of cooperation of regional governments). The results also showed that habitat in the lower reaches or north of the YZR had degraded more than in the middle reaches or the south of YZR. Therefore, regional development should put more effort into environmental protection, curb population growth, and encourage green technology innovation. Inter-province cooperation is necessary when dealing with ecological problems. This study can serve as a scientific reference for regional wildlife protection and similar investigations in different areas.