Hongjiannao Lake is the largest desert freshwater lake in China and the world's largest breeding habitat for gulls, which is of great significance to the local ecological environment and the breeding of key protected birds, and was listed as a national key protected lake in 2012. This study uses Landsat series satellite remote sensing data from 1973 to 2019 in combination with the NDWI water body index and OSTU adaptive threshold methods to obtain a 46-year area dataset for the study area. On this basis, the temporal and spatial evolution of the lake and its coupling relationship with natural factors and human activities were studied. The results show that (1) during the period 1973–2019, Hongjiannao Lake has undergone three stages: slight shrinkage (1973–1997), sharp shrinkage (1997–2015), and expansion (2015–2019); (2) The shrinkage of the Hongjiannao Lake is mainly caused by anthropogenic factors, followed by natural factors. The anthropogenic factors mainly consist of the upstream river construction reservoirs, industrial development of water and vegetation growth increased water demand; (3) For the first time, the preliminary results of the conservation measures implemented since 2012 were analyzed. This is mainly reflected in the positive growth of the Hongjiannao Lake for the first time since its long-term shrinkage in 1997. This phenomenon is mainly due to measures such as artificially increasing rainfall and ecological water replenishment. Climate change (high evaporation, low precipitation) and human activities (construction of upstream water conservancy projects, coal mining, lagoon road construction, irrigation water use, etc.) are the key factors contributing to the changes in lake area during the shrinkage period. It is suggested that the study area should carry out artificial rain enhancement and surface ecological water replenishment to scientifically and rationally utilize water resources in the basin, effectively suppress the shrinkage of Hongjiannao Lake, and achieve long-term sustainable restoration of the wetland ecology.