Calcium oxalate (CaOx) crystals are a major component of human kidney crystals and can induce renal tubular inflammation and damage, ultimately leading to renal calcium deposits and kidney stone formation. Umbelliferone (Umb) is a common coumarin compound. In this study, we used in vivo, in vitro experiments and network pharmacology were performed to assess the therapeutic effects of Umb on kidney stones and investigate its pharmacological mechanism. First, we established cellular and mouse models of calcium oxalate renal calcinosis, and we found that Umb reduces renal crystalline deposits, as well as the inflammation and damage they cause. Subsequently, we screened the PI3K/AKT signalling pathway via network pharmacology and experimentally demonstrated that Umb exerts its protective effects through the PI3K/AKT signalling pathway. Finally, molecular docking techniques and experiments were used to find out that Umb acts directly on PIK3CA to play its role.Our results indicate that Umb alleviates inflammation and injury by attenuating renal autophagy induced by kidney stones via the PI3K/AKT pathway.