The hepatitis C virus (HCV), the most predominant cause of liver failure worldwide, is associated with the development of diabetes mellitus (DM) and insulin resistance (IR), both in vivo and in vitro. DM and IR aggravate the rate of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Most studies have revealed that patients with HCV are at a greater risk of developing type 2 diabetes (T2D), compared with controls or patients with hepatitis B. In the same way, patients with T2D are highly prone to severe HCV clinical outcomes and increased progression to fibrosis and cirrhosis, ultimately leading to HCC. HCV interferes with the insulin-signaling pathway by modulating cellular gene expression such as up-regulation of inflammatory cytokine tumor necrosis factor-α, hypophosphorylation of insulin receptor substrate-1 and -2, phosphorylation of protein kinase B (Akt), up-regulation of gluconeogenic genes, accumulation of lipids, and targeting of lipid storage organelles. Owing to the pathological association between HCV and DM, the possibility of HCV eradication, resulting in reduced morbidity and mortality rate due to T2D, cannot be ruled out. HCV diabetes-associated IR can be targeted for HCV therapy. However, few such studies have revealed that IR minimizes (interferes with) the response rate of interferon/ribavirin treatment.