Ischemia-reperfusion injury is a leading cause of acute kidney injury (AKI), which is characterized by high morbidity and mortality, as well as a substantial risk of progression to chronic kidney disease (CKD). Although supportive care has improved considerably, effective disease-modifying therapies are still lacking. Therefore, the development of new therapeutic drugs for ischemic AKI is crucial. Active metabolites derived from medicinal plants, owing to their low toxicity and multi-target characteristics, are promising candidates for ischemic AKI therapy. This study reviews the pathogenesis of ischemic AKI from multiple dimensions, including metabolic disturbances, oxidative stress, inflammation, endoplasmic reticulum stress, mitochondrial dysfunction, and several forms of regulated cell death (e.g., ferroptosis, apoptosis, pyroptosis). It also summarizes plant metabolites (polyphenols, phenylpropanoids, terpenoids, saponins, alkaloids, and extracts) that can ameliorate ischemic AKI by targeting the aforementioned mechanisms. These metabolites exert their protective effects by modulating key signaling pathways (e.g., Nrf2/HO-1, NF-κB, PI3K/Akt). However, further mechanistic studies, standardization, and well-designed clinical trials are essential for their use and to ensure their integration into clinical practice as effective therapeutic options.