The development of resistance significantly reduces the efficacy of targeted therapies, such as sunitinib, in renal cell carcinoma (RCC) patients, emphasizing the need for novel therapeutic agents. Natural products, known for their diverse chemical structures and mechanisms of action, offer promising anti-tumor potential with favorable safety profiles and lower toxicity compared to synthetic drugs. 2-Undecanone, a natural compound extracted from Houttuynia cordata Thunb., has demonstrated anti-tumor effects, but its specific role in RCC treatment remains unclear. In this study, we integrated network pharmacology with in vitro experiments to explore the mechanisms underlying 2-Undecanone's effects on RCC. Our results reveal that 2-Undecanone effectively inhibits RCC cell viability, proliferation, and migration. Mechanistically, we discovered that 2-Undecanone induces ferroptosis in RCC cells by promoting reactive oxygen species (ROS) generation, intracellular Fe2+ accumulation, glutathione (GSH) production, lipid peroxidation, and modulation of the STAT3/GPX4 signaling pathway. Furthermore, 2-Undecanone lowers the IC50 value of sunitinib in RCC cells, enhancing their sensitivity to this targeted therapy. Additionally, 2-Undecanone potentiates sunitinib-induced ferroptosis. In summary, our research reveals that 2-Undecanone enhances the sensitivity of RCC cells to sunitinib through targeting the STAT3/GPX4 pathway, providing new insights into potential therapeutic strategies for RCC.