Oral anticoagulants are commonly prescribed but high risk to cause adverse events. Skilled drug interaction management is essential to ensure safe and effective use of these therapies. Clinically relevant interactions with warfarin include drugs that modify cytochrome 2C9, 3A4, or both. Drugs that modify p-glycoprotein may interact with all direct oral anticoagulants, and modifiers of cytochrome 3A4 may interact with rivaroxaban and apixaban. Antiplatelet agents, nonsteroidal anti-inflammatory drugs, and serotonergic agents, such as selective serotonin reuptake inhibitors, can increase risk of bleeding when combined with any oral anticoagulant, and concomitant use should be routinely assessed. New data on anticoagulant drug interactions are available almost daily, and therefore, it is vital that clinicians regularly search interaction databases and the literature for updated management strategies. Skilled drug interaction management will improve outcomes and prevent adverse events in patients taking oral anticoagulants.