Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Sorafenib is a multi-tyrosine kinase inhibitor used to treat HCC. However, it has many side effects and induces resistance. Esculetin is a natural compound with reported anticancer activity. This study was designedto assess the chemotherapeutic effects of the sorafenib and esculetin combination on human HCC cells.Stock solutions from sorafenib and esculetin in DMSO were prepared and then diluted by DMEM to obtain the required working concentrations. HepG2 and Huh-7 cells have been selected as in vitro model of HCC.Cytotoxicity was evaluatedusing an MTT assay. We performed flow cytometry analysis and scratch assay to assess apoptosis and migration. Finally, we quantifiedvascular endothelial growth factor (VEGF), VEGFR-2, EGFR, NF-κB, and Ki-67, PI3K, p38MAPK levels through ELISA, whileHRAS and ERK2 gene expressionwere detected through RT-PCR.The sorafenib and esculetin combination exerted a potent synergistic anti-tumor effect by modulating the EGFR and VEGF-RAS/ERK/PI3K/NF-κBaxes associated with significant upregulation of the apoptotic p38MAPK/caspase-3 axis, modulation of pI3k/p38MAPK crosstalk and inhibition of the proliferation marker Ki67.This study paves the way for using esculetin as good adjuvant to sorafenib as a promising future treatment for hepatocellular carcinoma.