The development of resistance in hepatocellular carcinoma (HCC) cells limits the effectiveness of sorafenib, but combination therapy with other drugs may have a positive effect. However, the effect of ropivacaine combined with sorafenib on the treatment of HCC cells and its potential regulatory mechanisms remain unclear. The proliferation and apoptosis of HCC cells treated with ropivacaine, sorafenib, and ropivacaine plus sorafenib were analyzed by cell-counting kit 8 and flow cytometry. The protein levels were measured by Western blot. The antitumor effect of ropivacaine, sorafenib, and their combination was verified by a tumor xenograft model. Ropivacaine and sorafenib markedly impeded the viability of HCC cells in a concentration-dependent manner. Compared with ropivacaine or sorafenib treatment alone, ropivacaine and sorafenib combination treatment impeded HCC cell proliferation, facilitated apoptosis, enhanced cleaved caspase-3, cleaved caspase-9, and cyclin D1 protein expression, while it reduced IL-6 and p-STAT3 expression and inhibited tumor growth in vivo. Importantly, the activation of the IL-6/STAT3 pathway could reverse the repressive or stimulative effects of ropivacaine and sorafenib on the proliferation and apoptosis in HCC cells. In summary, ropivacaine synergistically induces sorafenib-stimulated apoptosis of HCC cells via the IL-6/STAT3 pathway. Ropivacaine is a potential drug for the treatment of HCC when combined with sorafenib.