As a broad-spectrum oral small molecule inhibitor targeting multikinase, sorafenib is currently approved for the clinical treatment of several types of cancer as a single agent. A considerable number of clinical trial results have indicated that combination therapies involving sorafenib have been shown to improve treatment efficacy and may lead to novel therapeutic applications. Ursolic acid (UA), a natural pentacyclic triterpene compound extracted from a great variety of traditional medicinal plants and most fruits and vegetables, exhibits a wide range of therapeutic potential, including against cancer, diabetes, brain disease, liver disease, cardiovascular diseases, and sarcopenia. In the present study, we investigated the antitumor effects of sorafenib in combination with ursolic acid and found that the two agents displayed significant synergistic antitumor activity in in vitro and in vivo tumor xenograft models. Sorafenib/UA induced selective apoptotic death and ferroptosis in various cancer cells by evoking a dramatic accumulation of intracellular lipid reactive oxygen species (ROS). Mechanistically, the combination treatment promoted Mcl-1 degradation, which regulates apoptosis. However, decreasing the protein level of SLC7A11 plays a critical role in sorafenib/UA-induced cell ferroptosis. Therefore, these results suggest that the synergistic antitumor effects of sorafenib combined with ursolic acid may involve the induction of Mcl-1-related apoptosis and SLC7A11-dependent ferroptosis. Our findings may offer a novel effective therapeutic strategy for tumor treatment.