As promising noninvasive biomarkers of diverse disease stages, circulating miRNAs have emerged as promising biomarkers. Micro RNA 21 expression is also correlated with the proliferation, invasion, and metastatic properties of malignant cells. Therefore, mitogen-activated protein kinases (MAPKs), including a group of serine and threonine kinases, have been identified. They are vital signaling components that alter the external stimuli of several  responses at the level of the cell , like proliferation, survival, differentiation, and migration. Hence, because of their essential roles in these cellular functions, decotrol MAPKs contribute to the development of many cancers as hepatocellular carcinomas (HCCs). A study was performed here to investigate miR-21 expression profiles and mitogen-activated protein kinase-kinase 3 (MAPKK3) in Hepatitis C virus (HCV)-related HCC patients. The expression of miR-21 was assessed in the plasma of 10 healthy subjects, 20 patients with cirrhosis, and 20 patients with HCC using RT-PCR. Then, MAPKK3 was detected using enzyme-linked immunosorbent assay (ELISA) for all subjects. Compared to cirrhosis, HCC showed significantly higher levels of micro RNA 21 and MAPKK3. Additionally, a significant difference was observed in micro RNA 21 and MAPKK3 expression between the HCC and cirrhotic groups. Correlation analysis also revealed a significantly positive correlation between micro RNA 21 and MAPKK3 concentrations. Likewise, AFP correlation along with the micro RNA 21 or MAPKK panel was significantly correlated. In particular, results showed that miR-21 and MAPKK levels were higher in patients with similar number and tumor size of focal lesions. Thus, these results revealed that micro RNA 21 and MAPKK3 were biomarkers that can be accustemed to improve the diagnosis of HCC patients and that micro RNA-21 can be used as a separate biomarker for enhancing diagnostic precision.