Objective: Our objective was to evaluate the association between switching from warfarin to non-vitamin K oral anticoagulants (NOACs) and potential drug–drug interactions (DDIs), healthcare utilization, and expenditures in working-age adults with atrial fibrillation (AF). Methods: We conducted a retrospective cohort study using data from 2010 to 2015 for patients who switched from warfarin to NOACs (switchers) and those who continued to receive warfarin (non-switchers). We identified medications known or suspected to have clinically significant interactions with NOACs or warfarin. We used multivariate logistic regression, negative binomial, and generalized linear models to evaluate the influence of switching to NOACs and of potential DDIs on inpatient visits, outpatient visits, number of outpatient visits, and non-drug medical expenditures. Inverse probability of treatment weighting was also applied in analyses. Results: A total of 4126 patients with AF were included in the study. Switching to NOACs was significantly and negatively related to the number of outpatient, inpatient, and emergency room (ER) visits and non-drug medical expenditures. When potential DDIs were included in the models, switching remained significantly associated only with reduced inpatient and outpatient visits. Notably, having at least one potential DDI was associated with an increased likelihood of ER visits and the number of outpatient visits; it was also significantly and positively associated with non-drug medical expenditures. Conclusions: Relative to persistent warfarin use, switching to NOACs was associated with fewer inpatient, ER, and outpatient visits and lower non-drug costs. Potential DDIs were also strongly and positively associated with healthcare utilization and expenditures. Both are critical to consider in the management of AF in working-age adults.