Over the past half century, the Yangtze Plain of China has experienced rapid economic development. Lake reclamation (i.e., conversion of natural lake/wetland areas to agricultural/urban land or aquaculture, thereby reducing the area of natural waters) in particular has greatly contributed to meeting the increasing demands for food and urban development. However, until now, a comprehensive quantification and understanding of historical anthropogenic lacustrine exploitation in this region has been lacking, prohibiting assessment of the impacts of these activities. We used Landsat observations from 1973 to 2018 to track reclamation-induced changes in 112 large lakes (97.8% of the total lake area) in the Yangtze Plain. We show that 41.6% (6056.9 km²) of the total lake area has been reclaimed since the 1970s. The expansion of agricultural and built-up lands dominated the reclamation activities in the 1970s, while the increase of aquaculture zones has prevailed since the mid-1980s. Reclamation activities were closely connected to government policies and major socio-economic events and had strong impacts on lake hydrology, flood risk mitigation capacity, and water quality as revealed by satellite and in situ observations. This new quantitative understanding of anthropogenic reclamation and its associated impacts on Yangtze Plain freshwater lakes can underpin the development of strategies to reduce the impacts of lake reclamation on environmental quality. The study has also demonstrated the unique strength of using long-term series satellite images in tracking historical environmental changes in a substantial region of the world, and the methods used here are potentially extendable to other inland and coastal areas to understand similar human-environment interaction problems.