As an important part of the global ecosystem, wetlands and their dynamics greatly influence regional eco-environment systems. To understand the distributions, change processes and temporal-spatial characteristics of the wetlands of the inland river basin in an arid region (Heihe River Basin, HRB), this paper employed multi-source remote sensing data to facilitate multi-temporal monitoring of the HRB wetland using a wetland information extraction method. First, we performed monitoring of these wetlands for the years 2000, 2007, 2011 and 2014; then, we analyzed the variation characteristics of the spatial-temporal dynamics of the wetlands in the HRB over the last 15 years via the landscape dynamic change model and the transformation matrix. In addition, we studied the possible driving mechanisms of these changes. The research results showed that the total area of the HRB wetlands had decreased by 2959.13 hectares in the last 15 years (Since 2000), and the annual average loss was −1.09%. The dynamics characterizing the HRB wetlands generally presented a trend of slow increase after an initial decrease, which can be classified into three stages. From 2000 to 2007, the total wetland area rapidly decreased; from 2007 to 2011, the area slowly decreased; and from 2011 to 2014, the area gradually increased. The dynamic changing processes characterizing the wetland resources were ascribed to a combination of natural processes and human activities. The main driving mechanisms of wetland dynamic changes include climatic conditions, upper reach water inflows, population, water resources, cultivated area, and policy. The findings of this study can served as reference and support for the conservation and management of wetland resources in the HRB.