This chapter explores the integration of precision medicine into the prevention, diagnosis, and treatment of hepatitis C virus (HCV) infection across Africa and among populations of African descent. With Africa having the highest global HCV prevalence, particularly in Egypt and sub-Saharan regions, the application of tailored medical approaches is critical for combating this chronic viral disease. The chapter begins by discussing the promise of precision medicine, emphasising the role of viral genotyping, host genetic polymorphisms, and personalised treatment in optimising outcomes. It provides a comprehensive overview of HCV epidemiology in Africa, highlighting regional variations and emphasising the importance of robust data collection to guide intervention strategies. Transmission routes—including unsafe injections, dialysis, and blood transfusions—are analysed, alongside diagnostic challenges in asymptomatic cases. The role of serology, molecular diagnostics, and liver imaging in early detection is reviewed. Genotype distribution, especially the predominance of genotypes 1 and 4 in Africa, is discussed in relation to therapeutic responses to direct-acting antivirals (DAAs). The chapter then examines genetic predictors of treatment response, such as IL28B and IFNL3 variants, and explores polymorphisms associated with disease severity, including VDR, TLR, and PKR gene variants. Region- and country-specific case studies from North Africa and sub-Saharan Africa demonstrate varying epidemiological trends, healthcare capacities, and genetic research progress. The chapter also highlights the high burden and unique genetic features of HCV in African Americans, reinforcing the need for inclusive research. The chapter concludes by emphasising the necessity of personalised, genotype-informed treatment strategies and expanding access to affordable diagnostics and therapies to achieve the World Health Organisation (WHO) goal of HCV elimination by 2030.