BACKGROUND: Population-based studies have validated the significant associations between delirium and sarcopenia. Nonetheless, the causality remains ambiguous. This study aims to elucidate the causal associations between delirium and sarcopenia, as well as the causal effects of medication use on both conditions. METHODS: A bidirectional two-sample Mendelian randomization (MR) analysis was performed based on public genome-wide association studies (GWAS) data. Causal effects were evaluated through the inverse-variance weighted (IVW) method as the principal analysis, supplemented by the weighted median, weighted mode. Cochran's Q test, MR-Egger regression, MR-PRESSO test and leave-one-out were applied for sensitivity analyses. RESULTS: The IVW method indicated a causal relationship between genetically predicted low hand-grip strength and delirium (OR = 1.31, 95 % CI: 1.02-1.67, P = 0.032). Additionally, diuretics (OR = 1.05, 95 % CI: 1.03-1.07, P <
0.001) and glucocorticoids (OR = 1.06, 95 % CI: 1.01-1.12, P = 0.012) were causally associated with appendicular lean mass, and diabetes medications (OR = 1.04, 95 % CI: 1.02-1.06, P = 0.001) and immunosuppressants (OR = 1.05, 95 % CI: 1.02-1.09, P = 0.005) causally associated with low hand-grip strength. Alternative analytic methods yielded consistent results. Heterogeneity and horizontal pleiotropy were evident in associations between medication use and both delirium and sarcopenia, but the results remained consistent after excluding outliers. CONCLUSION: This study provided evidence of a causal relationship between genetically predicted low hand-grip strength and delirium. However, the analysis revealed that medication use did not appear to act as a mediating factor between these two conditions. Larger population-based studies are needed to validate these findings.