Background and Aims Regorafenib treatment for liver cancer inevitably presents side effects and limited efficacy. Programmed death-ligand 1 (PD-L1) monoclonal antibody can effectively block the "tumor immune escape mechanism" and exert significant anti-tumor effects. Therefore, this study was conducted to explore the anti-cancer effect of regorafenib combined with PD-L1 monoclonal antibody in a mouse model of transplanted liver cancer.Methods After establishing a liver cancer transplant model in Balb/C nude mice, the mice were treated with regorafenib (regorafenib group), atezolizumab (PD-L1 antibody group), regorafenib + atezolizumab (combination group), or saline (model group) for 4 weeks. Tumor volumes were dynamically measured in each group during the treatment period. After 4 weeks, the transplanted tumors were excised from the mice, and flow cytometry, TUNEL assay, and HE staining were used to detect CD4⁺ and CD8⁺ cell infiltration, apoptosis rate, and morphological characteristics of the tumor tissues. Additionally, qRT-PCR and Western blot were employed to detect the expression of CD31, vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (Ki-67), B-cell lymphoma 2 (Bcl-2), and Bax in the tumor tissues.Results There was no statistically significant difference in tumor volumes among the four groups of mice before treatment (P>0.05). At weeks 1, 2, 3, and 4 of treatment, the tumor volumes in each treated group were significantly smaller than those in the model group, and the tumor volume in the combination group was significantly smaller than those in the two monotherapy groups (all P<0.05). However, there was no significant difference in tumor volume between the two monotherapy groups (all P>0.05). The proportion of CD4⁺ and CD8⁺ cells in tumor tissues was significantly higher in each treated group than those in the model group, with the increase being in the order of regorafenib group <PD-L1 antibody group < combination group (all P<0.05). The apoptosis rate of tumor cells was significantly higher in each treated group compared to the model group, with the increase being in the order of regorafenib group <PD-L1 antibody group < combination group (all P<0.05). HE staining showed large, deeply stained, densely arranged nuclei in tumor cells of the model group, while various degrees of nuclear shrinkage, reduced cell numbers, and patchy necrosis were observed in the treated groups, with the most pronounced changes in the combination group. Compared to the model group, the expression levels of CD31, VEGF, Ki-67, and Bcl-2 mRNA and protein in tumor tissues were significantly lower in the treated groups. In contrast, the expression levels of Bax mRNA and protein were significantly higher. The extent of these changes was more pronounced in the combination group than in the two monotherapy groups, with no significant difference between the two monotherapy groups (all P>0.05).Conclusion Regorafenib combined with PD-L1 monoclonal antibody can effectively inhibit the growth of liver cancer, and the intensity is greater than that of either treatment alone. This effect may be achieved through the synergistic interaction of their different mechanisms of action.