Exploring spatio-temporal evolution and the laws of economic differences of river basin can provide a scientific basis for promoting the adjustment and optimization of the spatial structure of river basin economy, making regional coordinated development policies, and promoting the sustainable stability and high-quality development of river basin economy. Based on the combination of mathematical statistics analysis and exploratory spatial data analysis (ESDA), this paper takes county as the basic unit and GDP per capita as the measurement index to study spatial pattern evolution and the influencing factors of county economic differences in the Fenhe River Basin from 1995 to 2016. The results show that the absolute difference of county economy in the basin has shown a trend of rapid rise and then gradual decline, while the relative difference is characterized by the decline of fluctuation after the rise of fluctuation since 1995. The spatial differentiation characteristics of county economy is obvious, and there are distinct spatial and temporal evolutions, which forms the core area of basin economy centered on cities of Taiyuan and Xiaoyi, and the economic edge area is composed of Ningwu, Jingle, Loufan, Lanxian, Fenxi, Wanrong, etc. The "Core-Edge" characteristics of economic spatial structure is significant, and the difference of the economic development level between the core area and the edge area is obvious. From the perspective of spatial correlation, the county economy in the study area has obvious spatial positive correlation, which fluctuates with time. The hot and sub-hot areas of the county economy are mainly concentrated in the middle reaches of the river basin with Taiyuan and Xiaoyi as the center, while the upstream of the basin and the southern part of the downstream become cold and sub-cold areas. The center of gravity of the basin's economic space moves toward the southwest in the direction of the main axis, which is more obvious, and there is a certain degree of expansion in both the main axis and the auxiliary axis. But the expansion process is not the same, which is consistent with the strategy of actively promoting the urban spatial planning system of "One Core, One Circle and Three Groups" in Shanxi Province. Natural conditions and geographical location, regional resource endowment and industrial structure, population and urbanization level, as well as national policies and market environment are important factors that affect the evolution of county economic spatial pattern in the study basin. Among them, the agglomeration of population, the development of urbanization, the improvement of industrialization level and the expansion of market scale play a significant role in promoting the development of county economy, while limitation of terrain and the lack of regional market vitality will restrict and hinder the development of county economy in this region. The analysis results of multiple linear regression model show that the imbalance of population agglomeration and industrial development level are the main factors leading to the expansion of economic differences of county in the Fenhe River Basin.