Background: Acute kidney injury (AKI) is a common and potentially fatal complication encountered during a variety of kidney surgeries. Renal ischemia/reperfusion (I/R) injury is the predominant mechanism of AKI in this setting. Hence, controlling I/R injury is a key research imperative as it is directly related to the prognosis of patients. Summary: In the last decade, studies in vitro and in animal models have demonstrated that flavonoids can significantly alleviate I/R-induced AKI through a variety of pathways, including anti-oxidative stress, anti-inflammation, anti-cell death, inhibition of endoplasmic reticulum stress, and alleviation of mitochondrial dysfunction. Based on the extensive role of flavonoids in ischemia-reperfusion injury, the lack of drugs entering the clinic so far is a question worthy of consideration. Key Messages: This review summarizes the available evidence pertaining to the protective effect of flavonoids against renal I/R injury and discusses their potential clinical application in renal I/R injury.