The aim of our study is to investigate the protective effect of apigenin and the role of the JAK2/STAT3 signaling pathway in renal ischemia/reperfusion injury (IRI) in rats. For in vivo experiments, rat kidneys were subjected to 45min of ischemia, followed by 24h of reperfusion. The kidneys were pretreated for 24h with apigenin (4mg/kg) intraperitoneally in the absence or presence of the JAK2 kinase-specific inhibitor AZD1480 (30mg/kg). The serum creatinine and urea nitrogen levels were analyzed. Histologic examinations were evaluated. Expression of p-JAK2, p-STAT3, Bcl-2, Bax and Caspase-3 was detected by immunohistochemistry or western blot. For In vitro experiments, NRK-52E cells were exposed to I/R in the absence or presence of apigenin and JAK2 siRNA was used to explore JAK2/STAT3 activity. Cell viability, cell apoptosis and expression of p-JAK2, p-STAT3, Bcl-2, Bax and Caspase-3 were examined in NRK-52E culture after I/R. Consequently, apigenin conferred a renoprotective effect on the kidneys against IRI, as evidenced by decreased serum creatinine and urea nitrogen, mitigated renal histologic damage, improved NRK-52E cell viability and a decreased apoptotic index, including up-regulation of the anti-apoptotic protein Bcl-2 and down-regulation of the pro-apoptotic proteins Bax and Caspase3. However, AZD1480 and JAK2 siRNA blocked the apigenin-mediated renoprotective effects by attenuating the JAK2/STAT3 signaling pathway as well as abolished the effect of anti-oxidative stress and anti-apoptosis of apigenin. Our study demonstrates that apigenin pretreatment can protect against renal IRI via the activation of the JAK2/STAT3 signaling pathway.