BACKGROUND: Previous observational studies have reported a possible association between major depressive disorder (MDD) and abnormal cortical structure. However, it is unclear whether MDD causes reductions in global cortical thickness (CT) and global area (SA). OBJECTIVE: We aimed to test the bidirectional causal relationship between MDD and CT and SA using a Mendelian randomization (MR) design and performed exploratory analyses of MDD on CT and SA in different brain regions. METHODS: Summary-level data were obtained from two GWAS meta-analysis studies: one screening for single nucleotide polymorphisms (SNPs) predicting the development of MDD (n = 135,458) and the other identifying SNPs predicting the magnitude of cortical thickness (CT) and surface area (SA) (n = 51,665). RESULTS: The results showed that MDD caused a decrease in CT in the medial orbitofrontal region, a decrease in SA in the paracentral region, and an increase in SA in the lateral occipital region. C-reactive protein, tumor necrosis factor alpha (TNF-α), interleukin-1β, and interleukin-6 did not mediate the reduction. We also found that a reduction in CT in the precentral region and a reduction in SA in the orbitofrontal regions might be associated with a higher risk of MDD. CONCLUSION: Our study did not suggest an association between MDD and cortical CT and SA.