Following the basic law of epidemic spread, with the COVID-19 pandemic as an example, and using the partial least squares regression method, this study conducts an empirical analysis of the structural elements of epidemic transmission under conditions of inter-provincial openness in China by establishing an inter-provincial openness index system. This system comprises natural and social factors as transmission elements of COVID-19. It finds that aside from temperature and relative humidity, the rate of Wuhan’s inflow is directly related to a province’s COVID-19 incidence. Inter-provincial distance, daily passenger transport, and the proportion of equity investments reflect the proportion of Wuhan’s inflow into the provinces. These four elements reflect the scope of the epidemic. The urbanization rate, per capita GDP, business environment index, passenger density, and population density indirectly reflect the degree of population mobility in the province, which constitutes the transmission route of the epidemic. The theoretical framework of the structural elements of epidemic transmission under conditions of inter-provincial openness is constructed based on the analysis. In the process of preventing and controlling the spread of the virus, isolation of infectious sources is the most important factor. Under conditions of inter-provincial openness, limiting inter-provincial openness is the key to mitigating the spread of COVID-19.