Renal cell carcinoma (RCC) is the predominant form of kidney cancer. Despite the significant improvements in survival rates for advanced RCC patients due to targeted therapy and immunotherapy, challenges such as drug resistance and severe adverse reactions continue to hinder effective management. Therefore, there is an urgent need to identify new therapeutic agents for RCC. Natural products, derived from plants, animals, and microorganisms, are increasingly recognized for their potential in treating complex diseases such as cancer. Dendrobine, a natural product extracted from Dendrobium, holds significant anticancer potential. However, its role in anti-RCC therapy remains poorly understood. This study applied network pharmacology to explore the role of Dendrobine in RCC treatment, identifying STAT3 as a key target. Furthermore, a series of in vitro experiments confirmed that Dendrobine inhibits RCC cell growth. CCK-8 assays demonstrated that Dendrobine inhibits RCC cell viability in a concentration-dependent manner, with an IC50 of 142.5 mu M for 786-O cells and 146.5 mu M for A498 cells. Clonogenic formation assays and EdU staining confirmed that Dendrobine suppresses RCC cell proliferation. Wound healing and invasion assays showed that Dendrobine inhibits RCC cell migration and invasion. Hoechst 33342/PI co-staining demonstrated that Dendrobine induces apoptosis in RCC cells. Mechanistically, Western blot analysis revealed that Dendrobine targets the PI3K/Akt signaling pathway by inhibiting the expression of p-PI3K, p-Akt, and p-Erk. Overall, this study seeks to elucidate the underlying pharmacological mechanisms and provide new insights for potential therapeutic strategies in RCC.