Objective To explore the spatial cluster of incidence and changing trend of clustering area over time of hepatitis C in China from 2004 to 2020, so as to provide reference for identifying the key areas for scientific prevention and control of hepatitis C. Methods Data from the China Public Health Science Data Center Network Direct Reporting System were used for analysis. Software GeoDa was adopted to conduct the global and local spatial clustering analysis on various provinces in mainland China. Results The global spatial autocorrelation coefficients Moran’s I were all positive (all P<0.05), indicating that there was spatial cluster of hepatitis C incidence areas in various provinces across the country during this period. Local spatial autocorrelation analysis detected a total of 46 hot spots (areas with high incidence of hepatitis C) and 46 cold spots (areas with low incidence of hepatitis C). The hot spots concentrated mainly in Gansu, Tibet, Heilongjiang, Inner Mongolia, Jilin, Ningxia and Guangxi; while the cold spots were mainly in Jiangsu, Zhejiang, Shanghai, Anhui and Jiangxi. Conclusion Firstly, great attention should be paid to the hot spot areas of hepatitis C incidence, and less economically developed provinces as Gansu and Ningxia should have health resources priority. At the same time, surveillance on infectious disease of inbound personnel should be strengthened to stop cross-border transmission of infectious diseases timely, and prevent these area from becoming new high incidence areas of hepatitis C. Secondly, Public health education should be strengthened, awareness of active screening as well as increase of detection and cure rates of hepatitis C should be enhanced. Specific indicators for the prevalence, mortality, treatment and cure rates of hepatitis C should be refined. Based on the actual national conditions, the relevant successful international experiences can be drawn to help achieve the World Health Organization’s 2030 goal of eliminating the public health hazards of viral hepatitis.