<p>The pathological and physiological mechanisms for effectively mitigating ischemia–reperfusion (I/R) injury and preserving brain structure and function remain unclear. This study investigates the regulatory mechanism underlying cold-induced RNA-binding protein (CIRP)-mediated NF-κB pathway in cerebral I/R injury and neuronal inflammatory injury. The infarct volume of I/R CIRP^-/- mice was significantly mitigated, and the inflammatory factor IL-18 expression in mice serum and the NLRP3 and IL-1β expression in brain tissue was significantly decreased as opposed to the I/R WT mice. The in vitro outcomes manifested that inhibiting CIRP expression led to a significant hindrance in cell apoptosis, a significant drop in the inflammatory factors levels in the cell supernatant, and a significant decline in the expression of pyroptosis-linked proteins ASC, cleaved caspase-1, and gasdermin D (GSDMD) in cells. Following administration of the NF-κB pathway inhibitor PDTC, there was a significant hindrance in cell apoptosis, as well as a significant drop in the inflammatory factors levels IL-1β, TNF-α, and IL-18 in the cell supernatant. After treating BV-2 cells with HT22 cell conditioned medium under OGD condition, the content of LDH in BV-2 cells was increased. Intervention of CIRP expression in HT22 cells resulted in reduced damage to BV-2 cells and decreased expression of M1 marker CD86. CIRP may be involved in neuronal damage in I/R and in vitro OGD models via the NF-κB /NLRP3 pathway, and it may affect microglial polarization.</p>