Objective To observe the protective effect of dexmedetomidine (Dex) on renal ischemia reperfusion (IR) and to investigate whether the mechanism is through activation of α2 receptor/heat shock protein 70 (HSP70) thereby attenuating NOD‑like receptor‑related protein 3 (NLRP3)‑mediated cellular pyroptosis. Methods Sixty‑four SPF‑grade C57/BL6 male mice, 8‒10 weeks old, weighing 24‒26 g, were selected. According to the random number table method, they were divided into four groups (n=16): a sham‑operated (Sham) group, a renal IR group, an IR+Dex group, and an IR+Dex+atipamezole (ATI) (IR+Dex+ATI) group. A renal IR injury model was established by clamping the bilateral renal clitoris for 45 min and then restoring blood perfusion for 48 h in all groups except the Sham group. In the IR+Dex group, 50 μg/kg of Dex was intraperitoneally injected 30 min before clamping the renal clitoris and immediately after releasing the clamp, while 250 μg/kg of Dex was intraperitoneally injected at the same time in the IR+Dex+ATI group, and the other groups received the same amount of sterile normal saline. Then, blood samples and kidney tissues were collected from mice after 48 h of reperfusion. The serum creatinine (Cr) and urea nitrogen (BUN) levels were detected by an automatic biochemical analyzer to evaluate the renal function of mice. The hematoxylin‑eosin staining (H‑E staining) was used to evaluate the renal pathological damage, the expression of HSP70 was detected by immunohistochemistry. The levels of HSP70, NLRP3, gasdermin D (GSDMD), caspase‑1, apoptosis‑associated speck‑like protein (ASC), cleaved caspase‑1, and the N terminal fragment of GSDMD protein (GSDMD‑N) were detected by Western blot. The mRNA levels of HSP70, NLRP3, GSDMD, caspase‑1, ASC, interleukin (IL)‑1β, and IL‑18 were detected by real‑time fluorescence quantitative polymerase chain reaction (FQ‑PCR). Results Compared with the Sham group, the IR group showed increases in serum Cr and BUN levels, renal injury scores, HSP70 positive rate, the mRNA levels of HSP70, NLRP3, GSDMD, caspase‑1, ASC, IL‑1β and IL‑18, the protein levels of HSP70, NLRP3, GSDMD, caspase‑1, GSDMD‑N, cleaved caspase‑1 and ASC (all P<0.05). Compared with the IR group, the IR+Dex group presented decreases in serum Cr and BUN levels, renal injury scores, the mRNA levels of NLRP3, GSDMD, caspase‑1, ASC, IL‑1β and IL‑18, the protein levels of NLRP3, GSDMD, caspase‑1, GSDMD‑N, cleaved caspase‑1, and ASC (all P<0.05), as well as increases in HSP70 protein levels (all P<0.05). Compared with the IR+Dex group, the IR+Dex+ATI group showed increases in serum Cr and BUN levels, renal injury score, the mRNA levels of NLRP3, GSDMD, caspase‑1, ASC, IL‑1β and IL‑18, the protein levels of NLRP3, GSDMD, caspase‑1, GSDMD‑N, cleaved caspase‑1, and ASC (all P<0.05); as well as decreases in HSP70 positive rate, and the mRNA and protein levels of HSP70 (all P<0.05). Conclusions Dex can alleviate renal IR injury, possibly by activating α2 receptors to upregulate HSP70, thereby inhibiting NLRP3 inflammasome activation and the cascade of pyroptosis‑related reactions.