ABSTRACT Background Limited understanding exists regarding the hemorrhagic risk resulting from potential interactions between P-glycoprotein (P-gp) inhibitors and direct oral anticoagulants (DOACs). Utilizing the Food and Drug Administration Adverse Event Reporting System (FAERS) data, we analyzed hemorrhagic adverse events (AEs) linked with the co-administration of P-gp inhibitors and DOACs, aiming to offer guidance for their safe and rational use. Methods Hemorrhagic events associated with P-gp inhibitors in combination with DOACs were scrutinized from the FAERS database. Hemorrhagic signals mining was performed by estimating the reported odds ratios (RORs), corroborated by additive and multiplicative models and a combination risk ratio (PRR) model. Results Our analysis covered 4,417,195 cases, revealing 11,967 bleeding events associated with P-gp inhibitors. We observed a significantly higher risk of bleeding with the combination of apixaban and felodipine (ROR 118.84, 95% CI 78.12–180.79, additive model 0.545, multiplicative model 1.253, PRR 22.896 (2450.141)). Moreover, consistent associations were found in the co-administration analyzes of rivaroxaban with dronedarone and diltiazem, and apixaban with losartan, telmisartan, and simvastatin. Conclusion Our FAERS data analysis unveils varying degrees of bleeding risk associated with the co-administration of P-gp inhibitors and DOACs, underscoring the importance of vigilance about them in clinical practice.