Background: Modern pharmacological studies show that Epimedium sagittatum Maxim (EPI) has antioxidant, antiapoptotic, anti‐inflammatory effects. However, the effects of EPI on adriamycin‐induced nephropathy are unclear. Aim: The main purpose of this study is to investigate the effects of EPI on adriamycin‐induced nephropathy in rats. Methods: The chemical composition of EPI was detected by high performance liquid chromatography. Network pharmacology was used to collect the effects of EPI on adriamycin nephropathy; renal histological changes, podocyte injury, inflammatory factors, oxidative stress levels, apoptosis levels, and the PI3K/AKT signaling pathway were examined. Moreover, analyze the effects of icariin (the representative component of EPI) on adriamycin‐induced apoptosis and PI3K/AKT signaling pathway of NRK‐52e cells. Results: Network pharmacological results suggested that EPI may ameliorate adriamycin‐induced nephropathy by inhibiting inflammatory response and regulating the PI3K/AKT signaling pathway. The experimental results showed that EPI could improve pathological injury, renal function, podocyte injury, and inhibit inflammation, oxidative stress, apoptosis in adriamycin‐induced nephropathy rats through the PI3K/AKT signaling pathway. Furthermore, icariin inhibited adriamycin‐induced mitochondrial apoptosis in NRK‐52e cells. Conclusion: This study suggested that EPI ameliorates adriamycin‐induced nephropathy by reducing inflammation and apoptosis through the PI3K/AKT signaling pathway, icariin may be the pharmacodynamic substance basis for this effect. [ABSTRACT FROM AUTHOR]