AbstractBackgroundModern 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.AimThe main purpose of this study is to investigate the effects of EPI on adriamycin‐induced nephropathy in rats.MethodsThe 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.ResultsNetwork 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.ConclusionThis 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.