The middle and downstream sections of the Keriya River go deep into the hinterland of the Taklimakan Desert, and its morphological evolution is directly related to the spatial distribution efficiency and sustainable utilization of water resources in the basin. Based on Landsat series remote sensing images from 2000 to 2023, combined with meteorological, population, and land-use data, this paper analyzes the evolution characteristics and influencing factors of river morphology in the middle and downstream sections of the Keriya River. The results show that (1) the accuracy of the water area extracted by EWI, MNDWI, and NDWI was verified on the Google Earth Engine (GEE) platform. The water area extracted by MNDWI was the highest, and MNDWI was selected to extract the water area. (2) From 2000 to 2023, the middle and downstream sections of the Keriya River showed a trend of shrinking, straightening, and increasing gradient. The length of the river centerline decreased from 193.08 km to 173.86 km, the water area decreased from 37.21 km2 to 31.41 km2, and the river curvature decreased from 1.55 to 1.40, reflecting that the river tended to be flat. The river gradient is on the rise as a whole industry. (3) The change of river morphology is the result of the combined action of climate change and human activities. The increase of evaporation caused by rising temperature directly affects the river water area and the length of the center line, while population growth, cultivated land expansion, and construction land increase aggravate the water demand in the middle reaches, resulting in a decrease in downstream water volume. The impact of human activities is significantly higher than that of climate change. The scientific basis provided by this study aids in water resources management and ecological conservation in the Keriya River Basin.