Direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, and apixaban, have significantly fewer drug-drug interactions than warfarin. However, notable drug-drug interactions occur with strong CYP3A4 and P-glycoprotein (P-gp) inhibitors with DOACs, which clinicians need to consider when necessitating dosage adjustments and monitoring for their older patients. As a general principle, drugs that are inhibitors block the metabolic activity of one or more cytochrome P450 (CYP450) enzymes, and their effects usually occur immediately. Inducers increase CYP450 enzyme activity by increasing enzyme synthesis, thereby causing a delay before this increased enzymatic activity has an impact on metabolism. Each of the DOACs is a substrate for P-gp, an efflux transporter located in the gut mucosa; therefore, all DOACs are susceptible to drugs that induce or inhibit P-gp. Dabigatran requires efflux transportation by the P-gp; however, it is independent of the CYP450 enzyme system. Apixaban and rivaroxaban undergo minor hepatic metabolism by CYP enzymes. Alterations in varying rates of renal elimination of DOACs should be equally considered as possibly additive to the metabolic effects affecting outcomes from drug-drug interactions. Because drug product labeling provides specific guidance for the management of inhibitor interactions, it is highly recommended to consult this information before prescribing decisions are made. It is prudent for clinicians to exercise caution when coprescribing a DOAC and a strong CYP3A4 and/or P-gp inhibitor to minimize bleeding or in the case of a strong inducer (e.g., rifampin) to prevent the risk of thrombotic events. Pharmacokinetic DOAC drug-drug interactions are clinically important because patient harm may go unnoticed because of no international normalized ratio–equivalent testing and monitoring for DOACs as compared with warfarin. In a recent review, the most significant interacting drugs to cause bleeding events with DOACs were amiodarone and ritonavir, via inhibition of P-gp and CYP3A4. Conversely, a reduction in DOAC levels has been observed in some case reports and pharmacokinetic studies when used concomitantly with enzyme inducers (e.g., rifampin, carbamazepine), potentially resulting in therapeutic failure. It is advisable for all clinicians to periodically assess the patient’s medication regimen for drug-drug interactions when DOACs are prescribed. Advanced age, low body weight, renal impairment, or concomitant antiplatelet medications are additional factors that may affect the severity and outcome of DOAC drug-drug interactions.