Background Monocytes, critical components of the immune system, act as a link between innate and adaptive immunity. In the context of chronic hepatitis C virus infection, progressing to liver cirrhosis and hepatocellular carcinoma (HCC), monocytes differentiation into macrophages is thought to be crucial in altering microenvironment of the tumor. Recent data emphasizes the critical role of microRNAs (miRNAs) in the regulation of gene expression, influencing monocyte activation, immune responses, and cancer progression. Chronic liver disorders, such as HCV-related cirrhosis and HCC, have been linked to the dysregulation of certain miRNAs. Particularly miRNA let-7c has attracted attention because of its role in immune regulation and tumor biology. Objectives Here, we investigated the role of miRNA let-7c in controlling monocyte activation in chronic HCV-related cirrhosis and HCC, with an emphasis on its relationship to the immune-regulatory cytokine IL10. Methods The study included 54 patients with chronic HCV infection, divided into 3 groups; chronic HCV, liver cirrhosis, and HCC, as well as, 15 healthy individuals as controls. MiRNA let-7c and IL10 gene expression were assessed by RT-PCR, and CD16 and CX3CR1 expression on monocytes was assessed by flowcytometry. Results: The results showed that whilst IL10 expression was significantly elevated in HCC patients in comparison to HCV, cirrhosis and controls (P-value < 0.05), miRNA let-7c expression was gradually downregulated from chronic HCV to cirrhosis and HCC (P-value < 0.01). Furthermore, the percentage of CD16+CX3CR1+ monocytes was significantly increased the disease with disease severity, indicating their potential role in HCC progression. Conclusion Our findings suggest that decreased miRNA let-7c expression may contribute to monocyte activation and immune modulation in HCC via the regulation of IL10. IL10 overexpression in HCC may facilitate immune evasion and tumor progression, making it a promising biomarker for HCC diagnosis and monitoring. miRNA let-7c and CD16+CX3CR1+ monocytes could be valuable biomarkers for following the development of cirrhosis and HCC from a persistent HCV infection. Targeting the IL10 pathway could offer new therapeutic strategies for HCC treatment.