This study aimed to investigate how efflux pump activity contributes to high fluoroquinolone (FQ) resistance in Campylobacter jejuni and Campylobacter coli isolates and to evaluate the modulatory effects of a-tocopherol and aspirin on FQ phenotypic resistance profiles. Minimum inhibitory concentration (MIC) values were obtained for different FQ agents following exposure to different efflux pump inhibitors (EPIs), including PabN (50 mg/mL), which targets the cmeABC efflux system, and chlorpromazine (45 mg/mL) and verapamil (120 mg/mL), which target the MFS efflux system. The modulatory effects of aspirin (100 and 200 mg/mL) and a-tocopherol (4 and 10 mg/mL) on FQ resistance profiles were examined. PabN had no effect on the MIC values of all FQ agents, while MFS efflux system inhibitors reduced the resistance level of different FQ agents and achieved an effect nearly comparable with that of a-tocopherol (10 mg/mL). Aspirin exerted a dose-dependent excitatory effect on phenotypic resistance profiles, and this may raise concerns about its usage in both veterinary and clinical settings. While an efflux system other than cmeABC may play a role in FQ resistance in Campylobacter species, lipophilic substances may represent a new approach for controlling efflux pump activities.