Geographically isolated wetlands (GIWs) offer a diverse array of ecosystem services and contribute largely to landscape functions. Numerous studies have documented the substantial pressures on wetland ecosystems from both natural changes and human activities worldwide. However, the quantification of these impacts on GIWs remains scarce. This study presents an assessment of the spatiotemporal dynamics of GIWs in the downstream portion of the Nenjiang River Basin, Northeast China, over a 38-year period (1978-2015). We quantitatively evaluated the impacts of anthropogenic activities and natural changes using a five-stage wetland dataset (1978, 1990, 2000, 2008, and 2015) and four-stage (1990, 2000, 2010, and 2015) land use datasets. Our findings indicate that 86% of the GIWs in the study area have vanished, primarily replaced by unused land (28.39%) and farmland (54.90%). Anthropogenic activities were identified as the main cause of wetland loss from 1978 to 2008, whereas natural changes have played a more significant role in recent years of GIWs. Considering the ongoing regional trends of warming and drying, it is imperative to conserve and restore GIWs to maintain their ecosystem services for a broad spectrum of beneficiaries.