The δ opioid receptor (DOR), is the first cloned G protein-coupled receptor. Many recent studies on DOR functions have determined that the DOR is involved in the regulation of malignant transformation and tumor progression in multiple cancers. However, it is still unclear if the DOR is involved in the regulation of malignant transformation and tumor progression in hepatocellular carcinoma (HCC). The purpose of our study was to investigate the expression of the DOR in HCC and to determine its effect on progression to further understand the influence of the DOR on the biological characteristics of HCC. Higher expression of DOR was observed in liver tumor tissue/cells compared to normal liver tissue/cells. When DOR gene expression was silenced or inhibited, the proliferation of HCC cells was inhibited, and tumor cells underwent apoptosis, the cell cycle was arrested and tumor cell invasion and migration were significantly decreased. Nude mice inoculated with cells stably expressing low levels of DOR displayed reduced tumor formation rates and reduced tumor growth. In conclusion, DOR is highly expressed in HCC and is involved in HCC progression, suggesting that DOR is a potential target for HCC treatment.