Objective: To investigate the causal relationship between sepsis and cerebral cortex structure and average cortical thickness through two-sample Mendelian randomization, clarify whether sepsis affects the structure of the cerebral cortex, and provide more theoretical basis for the treatment and prevention of sepsis. Method: This study used statistical data on cerebral cortex structure and sepsis from public databases. The data on cerebral cortex structure and sepsis were downloaded from the Genome-Wide Association Study (GWAS) database. Two-sample Mendelian randomization analysis was performed using Inverse Variance Weighted (IVW), Mendelian randomization-Egger (MR-Egger), weighted median, simple mode, and weighted mode methods. Result: We found that sepsis is related to the surface area of the lingual gyrus (β=31.19; 95% CI: 5.88-56.50; p=0.02), and sepsis is related to the surface area of the cuneus cortex (β=26.42; 95% CI: 2.94-49.89; p=0.03), while reverse Mendelian randomization had no impact. Conclusion: Sepsis has a direct causal relationship with the surface area of the cuneus cortex, providing a new direction for the prognosis and diagnosis of brain dysfunction in sepsis.