Background: Since warfarin has a very narrow therapeutic index, the interaction between warfarin and antidepressants is very critical and has potentially severe consequences. It is unclear whether clinicians have sufficient knowledge about the risk of bleeding when warfarin and antidepressants are used concomitantly. Objective: In this systematic review, we discuss the main considerations when using warfarin with antidepressants. Methods: The information about warfarin-antidepressant interactions was obtained from Google Scholar®, PubMed/MEDLINE® and a hand search of the published literature. The following research terms which were systematically combined with each other to find articles: warfarin, anticoagulant, interactions, antidepressant (and each antidepressant name individually), SSRI, SNRI, TCA, MAOI. Results: Several possible mechanisms that can cause bleeding when antidepressants and warfarin are used concomitantly, have been discussed. According to the available data, sertraline and citalopram/ escitalopram are safer antidepressants to use with warfarin, whereas fluoxetine and fluvoxamine have a higher interaction potential with warfarin. The remaining antidepressants appear to lie somewhere in between and have little empirical data to guide the clinicians. Conclusion: It is recommended that when an antidepressant is prescribed to a patient using warfarin, patient’s international normalized ratio (INR) level should be checked regularly. In this review, the interaction between warfarin and antidepressants, including new ones, were evaluated inclusively and in detail.