Septic encephalopathy (SE) represents a severe inflammatory syndrome linked to elevated septic mortality rates, lacking specific therapeutic interventions, and often resulting in enduring neurological sequelae. The present investigation endeavors to elucidate the involvement of C-X-C Motif Chemokine Receptor 2 (CXCR2) in the pathogenesis of SE and to explore the potential of CXCR2 modulation as a therapeutic avenue for SE. Employing a murine SE model induced by lipopolysaccharide (LPS) administration, CXCR2 knockout mice and the CXCR2 inhibitor SB225002 were utilized to assess neutrophil recruitment, endothelial integrity, and transendothelial migration. Our findings substantiate that either CXCR2 deficiency or its inhibition curtails neutrophil recruitment without impacting their adhesion to cerebral endothelial cells. This phenomenon is contingent upon endothelial CXCR2 expression rather than CXCR2’s presence on neutrophils. Furthermore, the CXCR2 blockade preserves the integrity of tight junction protein ZO-1 and mitigates F-actin stress fiber formation in cerebral endothelial cells following septic challenge. Mechanistically, CXCL1-mediated CXCR2 activation triggers cerebral endothelial actin contraction via Rho signaling, thereby facilitating neutrophil transmigration in SE. These observations advocate for the potential therapeutic efficacy of CXCR2 inhibition in managing SE.