Fibroblast growth factor 8 (FGF8), a member of the fibroblast growth factor (FGF) family, is upregulated in several human cancers, including HCC (HCC). Previous studies have demonstrated that FGF8 increased cell growth and invasion of tumor cells. In the present study we investigated whether FGF8 is involved in the cell proliferation and resistance to several drugs in human HCC cells. We stably overexpressed FGF8 by lentiviral transfection. In addition, we also added recombinant FGF8 instead of stably overexpressing FGF8 in human HCC cells. Stable overexpression of FGF8 or exogenous recombinant FGF8 resulted in significantly enhanced cell proliferation in human HCC cells. With the use of CellTiter-Glo assay for the determination of cell viability, we found that FGF8 increased the resistance to epidermal growth factor receptor (EGFR) inhibitors in human HCC cells. Additionally, the expression of EGFR was also upregulated by stably overexpressing FGF8 or exogenous recombinant FGF8. Yes-associated protein 1 (YAP1) was reported to upregulate the expression of EGFR. Moreover, we also found that FGF8 increased the expression of YAP1 and knockdown of YAP1 eliminated the upregulation of EGFR and the resistance to EGFR inhibition induced by FGF8. Our study provides evidence that FGF8 plays an important role in the resistance to EGFR inhibition of human HCC cells.