This study aimed to determine the influence of proton pump inhibitors (PPIs) on the pharmacokinetics of voriconazole and to characterise potential drug-drug interactions (DDIs) between voriconazole and various PPIs (omeprazole, esomeprazole, lansoprazole and rabeprazole). Using adjusted physicochemical data and the pharmacokinetic (PK) parameters of voriconazole and PPIs, physiologically based pharmacokinetic (PBPK) models were built and were verified in healthy subjects using GastroPlusTM to predict the plasma concentration-time profiles of voriconazole and PPIs. These models were then used to assess potential DDIs for voriconazole when administered with PPIs. The results indicated the PBPK model-simulated plasma concentration-time profiles of both voriconazole and PPIs were consistent with the observed profiles. In addition, the DDI simulations suggested that the PK values of voriconazole increased to various degrees when combined with several PPIs. The area under the plasma concentration-time curve for the time of the simulation (AUC0-t) of voriconazole was increased by 39%, 18%, 12% and 1% when co-administered with omeprazole, esomeprazole, lansoprazole and rabeprazole, respectively. Omeprazole was the most potent CYP2C19 inhibitor tested, whereas rabeprazole had no influence on voriconazole (omeprazole > esomeprazole > lansoprazole > rabeprazole). However, in consideration of the therapeutic concentration range, dosage adjustment of voriconazole is unnecessary regardless of which PPI was co-administered.