Wetlands are known as the “kidneys of the earth” and play an important role in regulating climate, preventing floods and storing water, protecting biodiversity and purifying water sources. In recent years, with global environmental changes and interference from human activities, wetlands around the world are experiencing rapid and large-scale degradation. The degradation and loss of wetlands will have a negative impact on the human living environment, and are also an important reason for the frequent occurrence of natural disasters such as floods and typhoons. Therefore, wetland protection has become a hot issue of concern around the world. Xiaoxing’an Mountains are located in the mid-temperate zone of China and have developed many wetlands with unique ecological functions. However, over the past few decades, wetlands have been damaged by a series of production and construction activities such as agricultural reclamation and deforestation, as well as the impact of environmental changes. The spatio-temporal changes and driving mechanism of the herbaceous wetlands, shrub wetlands, and forest wetlands were explored in the Xiaoxing’an Mountains in 1975, 1985, 1995, 2005, and 2015, using the methods of standard deviation ellipses and geographical detectors. Results indicated that: ① The areas of herbaceous wetlands, shrub wetlands, and forest wetlands in Xiaoxing’an Mountains has decreased during forty years. The shrub wetlands had the lowest wetland rate and the area of herbaceous wetland lost the most. ② The wetland centroids of herbaceous wetlands, shrub wetlands, and forest wetlands all were shifted to the northwest by varying degrees, and the centroid of forest wetland had the longest migration distance. ③ The wetland loss had spatiotemporal differentiation. The wetland loss was mainly caused by the interference of human activities from 1975 to 1995, and the increase of cultivated land area, grazing, and population growth were the main wetland loss drivers in the northern and central part of the Xiaoxing’an Mountains, and the southern wetlands loss in the Xiaoxing’an Mountains was caused by the increase in the cultivated land area, coal mining, and population growth. From 1995 to 2015, the explanatory power of changes in the natural environment for wetland loss became more important, and the impact of natural environmental factors such as annual freeze-thaw thickness and annual precipitation on the loss of wetlands gradually increased. During forty years, the loss of wetland was driven by the interference of human activities and changes in the natural environment. ④ The interaction between different driving factors promoted the loss of wetlands. The results provide theoretical support for the protection of wetlands in the alpine regions of northern in China.