Prostaglandin E2 (PGE-2) is synthesised by cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). PGE-2 exhibits pro-inflammatory properties in inflammatory conditions. However, there remains limited understanding of the COX-2/mPGES-1/PGE-2 pathway in Angiostrongylus cantonensis-induced meningoencephalitis. This study revealed several key findings regarding the activation of the COX-2/mPGES-1/PGE-2 pathway and its correlation with eosinophilic meningoencephalitis induced by A. cantonensis infection. Immunostaining revealed an increase in the expression of COX-2 and mPGES-1 in the subarachnoid space and glial cells compared to control subjects. Inhibition of the NLRP3 inflammasome by small interfering RNA (siRNA) blocked extracellular secretory proteins (ESPs) stimulated COX-2, mPGES-1 and PGE-2 in microglia. MCC950, an NLRP3 inhibitor, inhibited the levels of the COX-2, mPGES-1, and PGE-2 proteins induced by A. cantonensis in mice. Treatment of mice infected with A. cantonensis with the COX-2 inhibitor NS398 significantly reduced the levels of mPGES-1, PGE-2, and matrix metalloproteinase-9 (MMP-9) levels. Similarly, the mPGES-1 inhibitor MF63 significantly reduced PGE-2 and MMP-9 levels in A. cantonensis-infected mice. Administration of MCC950, NS398, or MF63 resulted in marked attenuation of blood-brain barrier (BBB) permeability and eosinophil counts in A. cantonensis-infected mice. These findings highlight the critical role of the COX-2/mPGES-1/PGE-2 pathway and its regulation by the NLRP3 inflammasome in the pathogenesis of eosinophilic meningoencephalitis induced by A. cantonensis infection. Furthermore, pharmacological interventions targeting this pathway, such as MCC950, NS398, and MF63, show promising therapeutic potential in mitigating associated inflammatory responses and disruption of the BBB. The results indicate that blocking NLRP3 using pharmacological (MCC950) and gene silencing (siNLRP3) methods emphasised the crucial involvement of NLRP3 in the COX-2/mPGES-1/PGE-2 pathway. This suggests that the activation of the COX-2/mPGES-1/PGE-2 axis in response to A. cantonensis infection may be mediated through a mechanism involving the NLRP3 inflammasome.