Abstract Objectives To describe the prevalence, temporal and regional trends in prescribing direct oral anticoagulants (DOACs) in conjunction with interacting medications. Methods We performed a cross-sectional study of pharmacy dispensing data in the Foundation for Pharmaceutical Statistics (SFK) registry on patients who have had a prescription for a DOAC filled at one of 831 randomly selected pharmacies in the Netherlands between Jan 2014–Jan 2019. Results We identified 99,211 patients who had a first DOAC prescription filled. Mean age was 71.6 ± 10.9 years, 58% were male. In 2014, 8,293 patients were treated with DOACs, in 2018, 35,415 were newly started on a DOAC. In 2018, the use of apixaban was most common (52%) in the Eastern region, whereas rivaroxaban was most frequently prescribed (32–48%) in the other regions. At time of first prescription, the vast majority (99.3%) used ≥ 1 concomitant interacting drug, and 3.2% used ≥ 3 interacting medications. Most common were digoxin (37.8%), atorvastatin (31.5%), verapamil (13.7%) and amiodarone (9.7%). While the number of interacting medications remained unchanged over time (median 1, interquartile range 1–1), there was a notable decrease in antiarrhythmic medications and an increase in non-cardiovascular interacting medications (e.g. dexamethasone from 0.9% to 7.1%, antiepileptic drugs from 2.5% to 3.8%, and haloperidol from 0.5% to 2.2% in 2014 and 2018, respectively). Conclusion DOAC use has quadrupled in Dutch clinical practice over the 5‑year period from 2014 to 2018. While the number of patients who take interacting medications remained stable, the profile of interacting medications has changed over time from cardiovascular to medications affecting other organ systems.