In spite of rapidly developing direct acting antiviral treatments of HCV, the incidence of hepatocellular carcinoma (HCC) in Egypt is still rising. Our objectives were to assess the diagnostic performance and the predictive value of serum MMP-9 in HCV-related chronic liver disease patients pre- and post DAAs therapy. The MMP-9 levels were measured by ELISA in sera of 84 patients with HCV-related chronic liver diseases and 20 healthy controls. The HCC patients presented the highest MMP-9 levels in comparison with patients with liver cirrhosis (LC) and healthy controls (P < 0.0001). For discriminating LC patients from healthy individuals, MMP-9 ROC curve showed AUC = 0.948 with P < 0.0001, using cutoff level 512.4 ng/L, for discriminating HCC patients from non-HCC individuals, it showed AUC = 0.830 with P < 0.0001 using cutoff value 730.9 ng/L, for discriminating LC patients from HCC patients, it showed AUC = 0.703 with P < 0.0001 using cutoff value 1348.4 ng/L and for discriminating HCV-treated HCC patients from HCV-untreated HCC patients, it showed AUC = 0.813 with P < 0.001 using cutoff value 785.2 ng/L. The MMP-9 levels were significantly reduced in HCC patients after DAA therapy (P = 0.001), while no significant decreased in LC patients after DAA therapy (P > 0.05). In conclusion, serum MMP-9 comprises a promising biomarker for assessment of LC and HCC before and after DAA therapy of HCV patients. Further research on larger sample size may validate these findings and support our suggestions.