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The link between insulin resistance (IR) and hepatocellular carcinoma (HCC), especially in relation to HCV genotype-3 infection, is still poorly understood. In South Asian countries and among the peoples of the United States, this problem remains a major public health concern. According to previous studies, metabolic and viral interactomes have not been analyzed together, and hence this is a limitation of the study. This cross-sectional observational study involved 110 people, categorized into control (n=20), chronic hepatitis C (CHC) (n=45), and hepatocellular carcinoma (HCC) (n=45) groups. Clinical, biochemical, and metabolic parameters-HOMA-IR and HbA1c-were measured. The appropriate statistical tests were used for group comparisons. We performed molecular docking to investigate the interaction between the HCV genotype-3 core protein and human IRS-1 using ClusPro. HCC was independently associated with stage III-V fibrosis (AOR: 24.18), elevated HOMA-IR >4, a key indicator of insulin resistance (AOR: 3.53), and AFP >10 ng/mL (AOR: 3.71). Moreover, HbA1c >7% greater GGT and low albumin level were significantly higher in HCC group (P<0.05). Obese patients had higher IR markers, but CHC-to-HCC progression depended more on combined fibrosis and metabolic dysregulation than obesity alone. Docking analysis, there was a strong hydrophobic and electrostatic interaction between HCV core protein and IRS-1, with a binding energy of -1196.0 kcal/mol, indicating a strong and stable interaction between the two proteins. According to this study, it is possible that the presence of insulin resistance, advanced fibrosis, and viral persistence may interact biochemically and molecularly to contribute to hepatocellular carcinoma in cases of HCV genotype-3 infection.