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Major depression (MD) is a well-recognized risk factor for delirium. However, observational studies cannot provide direct evidence of causality between MD and delirium. This study explored the genetic causal association between MD and delirium using two-sample Mendelian randomization (MR). Genome-wide association study (GWAS) summary data for MD were obtained from the UK Biobank. GWAS summary data for delirium were obtained from the FinnGen Consortium. Inverse-variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode were used to perform the MR analysis. In addition, the Cochrane's Q test was used to detect heterogeneity in the MR results. Horizontal pleiotropy was detected using the MR-Egger intercept test and MR pleiotropy residual sum and outliers (MR-PRESSO) test. Leave-one-out analysis was used to investigate the sensitivity of this association. The IVW method showed that MD was an independent risk factor for delirium (P = 0.013). Horizontal pleiotropy was unlikely to bias causality (P > 0.05), and no evidence of heterogeneity was found between the genetic variants (P > 0.05). Finally, a leave-one-out test showed that this association was stable and robust. All participants included in the GWAS were of European ancestry. Due to database limitations, the MR analysis did not conduct stratified analyses for different countries, ethnicities, or age groups. We conducted a two-sample MR analysis and found the evidence of genetic causal association between MD and delirium. • A two-sample MR analysis was conducted to explore the causal effect between MD and delirium. • Inverse-variance weighted, MR Egger, weighted median, simple mode, and weighted mode were used to perform the MR analysis. • Heterogeneity and horizontal pleiotropy in the MR results were detected. • We found the evidence of genetic causal association between MD and delirium. [ABSTRACT FROM AUTHOR]