AIMS AND OBJECTIVES: Hepatitis C virus (HCV) infection is a significant risk factor for the development of hepatocellular carcinoma (HCC). Serum-derived circular RNAs (circRNAs) play several crucial roles in HCV and HCC. They represent a promising area of research for improving the diagnosis and understanding the mechanisms of HCV-HCC. This study aims to identify a serum-derived circular RNA (circRNA) diagnostic panel for HCV-HCC and to elucidate the regulatory mechanisms underlying their role in cancer progression. METHODS: In this study, data mining and in silico analysis were conducted to identify the role of circular RNAs (hsa_circ_0003288, circ-RNF13, hsa_circ_0004277, circANRIL, circUHRF1, hsa_circ_103047) and their associated biomarkers (IL-6 and NF-κB) in HCV-HCC pathogenesis. Additionally, RT-PCR was performed to assess their expression levels across different study groups (G0 = control, G1 = HCV, G2 = HCC, and G3 = HCV-induced HCC). RESULTS: The expression levels of circular RNAs, including hsa_circ_0003288, circ-RNF13, hsa_circ_0004277, circANRIL, circUHRF1, and hsa_circ_103047, as well as the biomarkers IL-6 and NF-κB, were significantly elevated in the G3 group compared to the G0 group. ROC analysis also revealed significantly different expression rates for G3 group and G0 group. CONCLUSION: The data revealed that cricRNAs panel (hsa_circ_0003288, circ-RNF13, circANRIL, circUHRF1, and hsa_circ_103047) could serve as a diagnostic biomarker and therapeutic target for HCV-induced HCC.