It is difficult to use traditional mathematical methods to analyze the relationship between regional macro-spatial structure and micro-individual behavior in reality. The entropy theory provides a new perspective for the cognition of human economic geography space. In particular, thermodynamic entropy is a state function that evaluates the degree of disorder of a spatial system and establishes a cognitive bridge between the macroscopic organization of the system and the number of microscopic states of existence. Information entropy provides an important quantitative method for confirming the attribute information of geographical things and their changing process and spatial organization. From the perspective of the isolated system → complex system → open complex giant system, this article focused on "entropy" in human economic geography from "social physics", gradually discussed the realistic performance of spatial entropy in human economic activities, and then reinterpreted the traditional location theory. Furthermore, this article also discussed the system foundation of spatial entropy theory represented by thermodynamic entropy and information entropy, and its relationship with modern mathematical methods represented by fractals. The purpose was to re-understand the human economic geography space, explore its research paradigm, and grasp its theoretical connotation under the background of the development of system science.