BACKGROUND: Hepatitis C virus (HCV) stands at the forefront of global elimination endeavors by 2030, highlighting the need for a nuanced exploration into disparities and vulnerabilities using innovative spatial epidemiological approaches. This study aimed to systematically review existing literature to summarize area-level factors associated with HCV infection and to examine the application of spatial and spatiotemporal analyses in HCV research. METHODS: A systematic search following PRISMA guidelines was conducted for peer-reviewed literature published between 2000 and 2023 using PubMed, Web of Science, Scopus, and Embase databases. The synthesis of area-level factors was organized according to four distinct categories of risk environments: social, economic, policy, and physical environments. RESULTS: Sixty-five studies were selected for this systematic review. 60% of the studies focused on the general population, while 20% of the studies targeted people who inject drugs. The area-level factors explored predominantly were characteristics of the social and economic risk environments. For instance, areas with a higher level of socioeconomic disadvantage, lower education attainment, higher population density, and located more remotely were associated with higher HCV infection rates. Additionally, some studies noted a significant correlation between the accessibility to harm reduction and healthcare services and HCV occurrence, testing, and treatment rates. Furthermore, spatial data exploration and cluster analysis methods were the predominant methods used to explore the nuanced spatial distribution of HCV infection. CONCLUSION: This review emphasizes the imperative of deciphering the complex interplay of area-level factors in HCV infection dynamics. Understanding the potential risk environment landscape of HCV could facilitate identifying vulnerable areas and communities. Additionally, the limited application of spatial analytics in HCV research highlights the untapped potential, emphasizing the need for enhanced spatial techniques to pinpoint priority areas for intervention.