The study analyzed data from the FAERS database from the 3rd quarter of 2010 to the 1st quarter of 2025 and compared bleeding events with direct oral anticoagulant (DOAC) monotherapy with their combination with antidepressants. The proportion of bleeding events was 31.00% (64,165/207,000) with DOAC monotherapy versus 57.92% (307/530) with combination therapy. Concomitant use of DOACs with antidepressants significantly increased the risk of bleeding with an OR of 1.45 (95% CI: 1.29–1.63). Selective serotonin reuptake inhibitors (SSRIs) had the highest risk with an ROR of 1.78 (95% CI: 1.54–2.04), with apixaban plus paroxetine showing the strongest signal (ROR 14.12, 95% CI: 7.62–26.15). The risk of nervous system bleeding was increased with an ROR of 1.86 (95% CI: 1.44–2.40). Mirtazapine significantly increased the risk of nervous system bleeding with an OR of 9.83 (95% CI: 4.92–19.67). The conclusion of the study states that co-administration of antidepressants and DOACs increases the risk of bleeding, especially in the nervous system. Doctors should be especially careful with SSRIs and mirtazapine.