Background & Aims: Our goals were to assess the predictive value of β-catenin, TNF-α, IL-21, and CA19-9 biomarkers and the diagnostic performance of a created model for early prediction of HCC after DAAs. Materials and Methods: ELISA was used to estimate serum levels of investigated biomarkers in 84 adult patients and 20 healthy individuals. To create an internally validated model predicts HCC development following DAA therapy of HCV patients, we employed linear regression analysis. Results: For HCV infected patients compared to the treated group, significant higher expression was detected in β-catenin (P < 0.0001) and TNF-α (P < 0.002) but a substantial increase was detected only in β-catenin (P < 0.0001) in LC. The AUC of β-catenin, TNF-α, IL-21, and CA19-9 for the potential diagnostic values of HCV-infected HCC patients from non-malignant individuals were 0.810, 0.829, 0.719, and 0.743; respectively. A newly developed MSB model based on β-catenin, TNF-α, IL-21, and CA19-9 had an AUC of 0.933 with sensitivity of 89.3%, and specificity of 93.7% at the best cut-off value of 3.09. Conclusion: The combination of β-Catenin, TNF-α, IL-21, and CA19-9 biomarkers constitute an outstanding diagnostic model for HCC (MSB model) that performs better pinpointing than each one alone.