This study tested the hypothesis that preactivated and disaggregated shape‐changed platelet (PreD‐SCP) therapy significantly protected rat kidney from ischemia‐reperfusion (IR) injury. Adult‐male Sprague–Dawley rats (n = 24) were equally categorized into Groups 1 (sham‐operated control [SC]), 2 (SC + PreD‐SCP), 3 (IR only), and 4 (IR + PreD‐SCP). By 72 hr after IR procedure, the circulatory levels of creatinine, blood urine nitrogen and inflammatory biomarkers (interleukin [IL]‐6/tumor necrosis factor [TNF]‐α), and ratio of urine protein to urine creatinine were significantly higher in Group 3 than in other groups and significantly higher in Group 4 than in Groups 1 and 2, but they showed no different between Groups 1 and 2 (all p < .001). The microscopic findings showed that the expressions of kidney injury score, cellular inflammation (MMP‐9/CD14//F4/80), and fibrotic area were identical to the circulatory inflammation, whereas the integrity of podocyte components (ZO‐1/synaptopodin/podocin) exhibited an opposite to circulatory inflammation among the four groups (all p < .0001). The protein expressions of inflammatory (TNF‐α/IL‐1ß/NF‐κB/iNOS/TRAF6/MyD88/TLR‐4), apoptotic/cell death (mitochondrial Bax/cleaved caspase‐3/p‐53), oxidized protein, mitogen‐activated protein kinase family (p‐38/p‐JNK/p‐c‐JUN), and mitochondrial‐damaged biomarkers displayed a similar pattern, whereas the antiapoptotic (Bcl‐2/Bcl‐XL) and integrity of mitochondrial biomarkers followed an opposite trend to circulatory inflammation among the four groups (all p < .001). PreD‐SCP therapy effectively protected the kidney against IR injury.