Lake wetlands (LWs) are essential components of the ecosystem and play an irreplaceable role in flood regulation, carbon fixation, and biodiversity maintenance. Continuous monitoring of LWs’ change is necessary in the context of increased human disturbance and climate change, particularly in Taihu Lake Basin, China, an area exposed to early human exploitation. Yet, long-time series of LWs detection in this region is still unavailable due to the data limitation. To quantify the spatiotemporal dynamics of LWs and the associated driving forces, we combined 236 historical topographic maps and thousands of Landsat satellite images from the 1910s to 2021 to delineate the centennial-scale changes of lake wetlands for the first time in this region. We also applied land use transitions and statistical analyses to quantitively explore the climatic and anthropogenic factors behind LWs variations. Our results document a dramatic decline in the area and number of LWs in the Taihu Lake Basin over the last century and a shift in the 2000s: Taihu Lake Basin has seen a total of 89.15% loss in lake littoral wetlands and a decrease of 14.5% in the whole lake wetlands area, with a net reduction of 68 (from 156 in the 1910s to 88 in the 2021) lakes. This decrease has been especially predominant during the 1910s–2000s, because of the policy initiatives for reclamation and aquacultural industries. The area and number of LWs have gradually been recovered since the 2000s as the country strengthened concern on the ecological restoration and sustainable development. The statistical results suggested that human activities played a dominant role in the LWs changes, with GDP and population explained 80.74% of the changes, coupled with climatic contribution of only around 20%. This long-term investigation will provide baseline information for future lake wetlands monitoring. Our findings could also provide a guidance for decision makers regarding water resources management, environmental protection and land-use planning in urban areas.