Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies in the world. Sox2 is a potential oncogene in the pathogenesis of HCC, however, the actual mechanisms of Sox2 functions in HCC has not emerged yet. In this study, we explored the expression, function and the relationship between Sox2 and PD-L1 in HCC. We found that both Sox2 and PD-L1 were expressed at a markedly higher level in HCC tissues in comparison to adjacent non-tumor tissues. Moreover, the expression levels of both genes were correlated with each other. Knockdown of Sox2 reduced the cell proliferation ability and induces apoptosis of HCC cells, suggesting the function of Sox2 in regulating both the cell proliferation and apoptosis. Noteworthy, the depletion of Sox2 also reduced the expression of PD-L1. Further analysis showed that there is a consensus Sox2 binding site in the promoter region of PD-L1. Through in vitro EMSA assay and in vivo chromatin immunoprecipitation assays, we demonstrated that Sox2 directly bound to the PD-L1 promoter through the consensus Sox2 motif. Further evidence by luciferase reporter assays revealed that Sox2 promoted the transcription activity of PD-L1 promoter region through the Sox2 motif. Collectively, our data provide a novel insight into the function and the interplay of Sox2 and PD-L1 in HCC.