This chapter aims to explore the clinical features, and differential diagnosis of neuropsychiatric manifestations in chronic hepatitis C (CHC), focusing primarily on depression and anxiety. The chapter discusses the impact of CHC treatment, particularly with interferon-α (IFN-α) therapy and newer all-oral direct-acting antivirals, on psychiatric symptoms, along with predisposing factors and screening tools for identifying depression and anxiety in CHC patients. Furthermore, the chapter addresses the barriers to CHC treatment in patients with substance and alcohol use disorders, offering methods to improve treatment outcomes in these populations. Lastly, it outlines the approach to managing neuropsychiatric symptoms during CHC treatment, including pharmacological interventions and follow-up monitoring strategies.