Solasonine (SS) has been shown to inhibit the proliferation of various malignant tumors, though its effects on lipid metabolism in tumor cells are less understood. This study investigated SS's anti-tumor mechanism in oral squamous cell carcinoma (OSCC) using lipidomics, cell, and animal models. SS inhibited the growth of CAL27 and WSU-HN30 cells and reduced tumor volume in mice. Lipidomic analysis revealed an increase in diglyceride (DG) and a decrease in triglyceride (TG) levels, alongside a reduction in diacylglycerol acyltransferase 1 (DGAT1), key to TG synthesis. SS also induced reactive oxygen species (ROS) production and mitochondrial damage. Molecular docking confirmed SS's interaction with DGAT1, suggesting it prevents DG to TG conversion, inhibiting OSCC proliferation.