<p>Cerebral ischemia reperfusion injury (CIRI) is a major contributor to mortality and disability in stroke patients. β-Caryophyllene (BCP) had been identified as a promising candidate for the treatment of CIRI. This study aimed to elucidate the mechanisms through which BCP exerts its therapeutic effects in CIRI.&#xa0;A rat model of cerebral ischemia was established by middle cerebral artery occlusion (MCAO) for 2&#xa0;h followed by reperfusion. Neurological function and cognitive outcome were evaluated using the water maze test and neurobehavioral test. Citrullinated histone H3 (cit-H3) and peptidyl arginine deiminase 4 (PAD4) in brain tissues were detected via Western blot and immunohistochemistry (IHC). The levels of inflammation and oxidative stress factors were evaluated using assay kits. Western blot was applied to examine the expression and activation of JAK2/STAT3 pathway.&#xa0;The results determined that BCP significantly improved neurological functions and promoted cognitive function recovery in CIRI rats. A significant increase of neutrophil extracellular traps (NETs) formation markers of cit-H3, PAD4, cf-DNA and MPO were found in brain tissues of CIRI rats, which were effectively reversed by the treatment of BCP. Moreover, the levels of phosphorylation of JAK2 and STAT3 in the brain tissue of CIRI rats were significantly elevated. In contrast, treatment with BCP significantly reduced the phosphorylation levels of JAK2 and STAT3. Moreover, coumermycin A1(CA1, JAK2 agonist) partially reversed the inhibitory effects of BCP on inflammation, oxidative stress levels, and NETs formation in CIRI rats.&#xa0;The levels of NETs formation in the brain tissues of CIRI rats were significantly elevated. BCP markedly inhibited the formation of NETs, reduced inflammation and oxidative stress levels. BCP facilitated the recovery of cognitive function and neurological functions by modulating the JAK2/STAT3 signaling pathway.</p> Graphical Abstract <p></p>