Ischemia-reperfusion (I/R) renal injury is considered the most common cause of acute kidney injury (AKI). The pathophysiology of I/R AKI involves a complex interplay among tubular epithelial cell injury, microcirculation dysfunction, and inflammation. Interleukin 18–binding protein (IL-18BP) is a natural inhibitor of IL-18 a cytokine that plays an important role in the pathogenesis of AKI. Therefore, we hypothesized that exogenous IL-18BP could protect against renal injuries after kidney I/R. Male Sprague-Dawley rats were divided into three groups: a sham operation group, I/R with vehicle injection, and I/R with IL-18BP injection. Rats underwent bilateral renal pedicle clamping, and IL-18BP or vehicle was administered just before reperfusion. Rats were killed 6, 24, and 72 h after reperfusion. After IL-18BP treatment, renal tubule epithelium showed reduced apoptosis and enhanced proliferation. For peritubular capillary (PTC) endothelium, apoptosis was inhibited, and there was an increase in PTC endothelium density. Macrophage infiltration was inhibited, and inflammatory cytokines were downregulated. Increased expression of vascular endothelial growth factor and decreased expression of thrombospondin 1 were also observed. Exogenous IL-18BP attenuated renal injury caused by I/R via inhibiting inflammation in the renal tissue and protecting tubular epithelium and PTC endothelium.