There are now anticoagulant choices with proposed advantages of non-vitamin K oral anticoagulants (NOACs) over warfarin being less routine monitoring and less drug interactions. Interacting medication can impact the efficacy and safety of anticoagulant therapy with management remaining clinically challenging. There have been limited studies comparing the potential for pharmacokinetic (PK) drug interactions between different anticoagulants. Therefore, the aim of this study was to compare potential PK interactions in patients with atrial fibrillation (AF) changing from warfarin to NOAC therapy. A retrospective analysis was conducted of patients with AF enrolled in a dedicated warfarin program but exiting this program to commence a NOAC. Patient data was collected, and concurrent medications were utilised to identify potential PK drug interactions with both warfarin and the chosen NOAC therapy. Patients were grouped according to the number of medications with potential PK interactions and comparisons made between groups. Of the 712 eligible patients who ceased warfarin to commence a NOAC, most commenced either apixaban (45.9%) or rivaroxaban (41.9%). When comparing warfarin to NOACs, there were significant differences in the proportion of patients taking no medication with potential PK drug interactions (46.9% vs 62.8%, p < 0.0001), and taking one (35.2% vs 28.5%, p = 0.0067) and two (14.5% vs 7.3%, p < 0.0001) potentially PK interacting medications. This study found when patients with AF were switched from warfarin to a NOAC, the potential for PK drug interactions significantly reduced but remained around 40%. Identifying and managing potential PK drug interactions with NOACs remains a priority to optimise clinical benefit of these anticoagulants.