BackgroundThe risk for thromboembolisms in nonsmall cell lung cancer (NSCLC) patients is increased and often requires treatment or prophylaxis with direct oral anticoagulants (DOACs). Small-molecule inhibitors (SMIs) to treat NSCLC may cause relevant drug–drug interactions (DDIs) with DOACs. Guidance on how to combine these drugs is lacking, leaving patients at risk of clotting or bleeding. Here, we give practical recommendations to manage these DDIs.MethodsFor all DOACs and SMIs approved in Europe and the USA up to December 2021, a literature review was executed and reviews by the US Food and Drug Administration and European Medicines Agency were analysed for information on DDIs. A DDI potency classification for DOACs was composed and brought together with DDI characteristics of each SMI, resulting in recommendations for each combination.ResultsHalf of the combinations result in relevant DDIs, requiring an intervention to prevent ineffective or toxic treatment with DOACs. These actions include dose adjustments, separation of administration or switching between anticoagulant therapies. Combinations of SMIs with edoxaban never cause relevant DDIs, compared to more than half of combinations with other DOACs and even increasing to almost all combinations with rivaroxaban.ConclusionsCombinations of SMIs and DOACs often result in relevant DDIs that can be prevented by adjusting the DOAC dosage, separation of administration or switching between anticoagulants.