Dexamethasone (DEX), a ligand for glucocorticoid receptor (GR), has long been used in the clinical practice due to its anti-inflammatory and immunosuppressive properties. Given that ischemia/reperfusion (IR)-induced renal injury is featured by the excessive immune response; the current study is therefore designed to address the impact of dexamethasone on IR-induced renal injury, a common disorder in the clinical settings. Precondition of mice with 4 mg/kg of dexamethasone significantly attenuated IR-induced injury as manifested by the improved renal function along with ameliorated pathological changes and suppressed inflammatory infiltration. Mechanistic studies revealed that dexamethasone promotes GR activation, and by which it attenuates the signals for PI3K/AKT activation. Attenuated PI3K/AKT signaling thus suppresses inflammatory response which then protects kidneys from IR-induced injury. All together, our data support that dexamethasone could be a good alternative therapy for prevention and treatment of IR-induced renal injury in the clinical practice.