Hepatitis is the seventh leading cause of mortality worldwide and is the only communicable disease where mortality is increasing, yet the long-term spatial–temporal variation at global scale and its possible causes, i.e., drivers, remain unknown. Firstly, this study employed the measure of spatial autocorrelation, Moran’s I, and the measure of local spatial cluster, Getis-Ord Gi*, to characterize the spatial variation of mortality due to hepatitis in 183 countries globally for years 2000, 2010, 2015 and 2019. Then, a novel spatial statistical method, named the Geographical Detector, was utilized to investigate eight possible influencing factors, i.e., risk factors, of the spatial–temporal variation of mortality due to hepatitis. The results showed significant disparities of hepatitis-related mortality rates among countries. Hot spots, representing locations with higher mortality rates, were consistently observed in Africa, East Asia, and Southeast Asia, while the cold spots, representing locations with lower mortality rates, were predominantly found in Europe and the Americas. Potential spatial drivers of hepatitis mortality, identified by geographical detector, include “health expenditure”, “universal health coverage”, and “per capita income”. However, “hepatitis B immunization” and “total population” were not identified as significant spatial drivers for hepatitis mortality The findings highlighted the critical role of socioeconomic factors in the variations in hepatitis mortality, and pointed out relative importance of increasing health expenditure, per capita income, and improve universal health coverage on alleviating global hepatitis-related mortality.