In the context of climate change and the intensification of population activities, differences in regional water resources are the main drivers leading to these resources’ unbalanced development. This problem can be addressed by exploring spatial differences and spatio-temporal patterns. Based on the spatio-temporal trends of grain production, social economy, population, and water resources in the Tarim River Basin from 2005 to 2020, this paper uses the barycenter model coupling situation model to analyze the evolutionary trend of the barycenter, spatial overlap and spatio-temporal coupling degree for each index. The results show the following: (1) The spatio-temporal distribution of grain production was larger in the east than in the west. Grain production increased by 18.10% across the basin, and the migration rate of the grain center of gravity (CG) was 16.61 km/a. (2) The spatio-temporal distribution of the economy was greater in the south than in the north, with a cumulative migration of 323.10 km to the southwest. During the study period, the population remained concentrated in the western portion of the basin, increasing 25.18% compared to the population prior to 2005. The spatial variation range of total water resources was small, showing a trend of slow increase from west to east. (3) The overlap between GDP and population was enhanced, with the coupling showing a slow rising trend. The overlap of water resources and grain space also increased and the consistency index was high. From 2011 to 2020, the average consistency index was 0.594 and the coupling degree of the two factors was enhanced. By combining grain production, economy, population, and water resources with the center of gravity model, this paper reveals the spatial differences of relevant factors in the Tarim River Basin, providing an important reference value for regional socio-economic development and the rational allocation of water resources.