Objective To explore the role of CORM-3 in alleviating cognitive dysfunction and cortical neuronal pyroptosis of rats exposed to hemorrhage shock and resuscitation. Methods One hundred and sixty-eight male SD rats, weighting 350-400 g, in accordance with random number table, were divided into 4 groups (n=42):sham-operated group, hemorrhage shock and resuscitation (H group), hemorrhage shock and resuscitation plus CORM-3 (CO group), hemorrhage shock and resuscitation plus iCORM-3 (ICO group). The rat hemorrhagic shock resuscitation models were established in H, CO and ICO groups:bleeding from femoral vein was performed to achieve mean arterial pressure of 25-35 mmHg (1 mmHg=0.133 kPa) for 60 min;and then, the collected blood was returned to the body within 15 min to reach the initial blood pressure level as resuscitation, and normal saline was injected if necessary. The rats in CO group were injected CORM-3 (4 mg/kg) via femoral vein after resuscitation, the rats in ICO group were injected iCORM-3 (4 mg/kg), and rats in the sham-operate group and H group were only injected equal amount of normal saline containing DMSO. Rats were sacrificed for cortex 12 h after end of resuscitation;CO content was assessed by gas chromatograph assay; Western blotting was used to detect the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and BTB-CNC homology 1 (Bach1) in the nuclear, and heme oxygenase-1 (HO-1), interleukin (IL)-1β and IL-18 in cytosol; and neuronal pyroptosis rate was detected by cleaved caspase-1-Cy3/neuron-specific nucleoprotein (NeuN)-FITC/DAPI. Thirty d after resuscitation, open field test was used to assess the cognitive ability of the rats. Results At 12 h after resuscitation, as compared with sham-operated group, rats in the H, CO and ICO groups had significantly increased CO content, neuronal pyroptosis, ratio of Nrf2/Bach1, and expressions of HO-1, IL-1β and IL-18, statistically longer time spending in the central square, significantly smaller times crossing the grid and times standing on the back legs (P<0.05). As compared with H and ICO group, CO group had significantly increased CO content, ratio of Nrf2/Bach1, and HO-1 expression, times crossing the grid, times standing on the back legs, but significantly decreased neuronal pyroptosis, expressions of IL-1β and IL-18, and time spending in the central square (P<0.05). Conclusion CORM-3 can reduce the neuronal pyroptosis rate and alleviate cognitive dysfunction in rats with hemorrhagic shock and resuscitation, whose mechanism may be related to the increase of HO-1 expression after up-regulation of Nrf2/Bach1 ratio.