Drug–drug interactions (DDIs) represent a significant concern in healthcare, particularly for patients undergoing polytherapy. DDIs can lead to a range of outcomes, from decreased therapeutic effectiveness to adverse effects. Salbutamol, a bronchodilator recommended for the treatment of respiratory diseases, is metabolized by cytochrome P450 (CYP) enzymes, which can be inhibited or induced by co-administered drugs. Studying DDIs involving salbutamol is crucial for optimizing drug therapy and preventing adverse outcomes. Here, we aimed to investigate CYP-mediated DDIs between salbutamol and fluvoxamine through in silico approaches. The physiologically based pharmacokinetic (PBPK) model of salbutamol was developed and validated using available clinical PK data, whereas the PBPK model of fluvoxamine was previously verified by GastroPlus. Salbutamol–fluvoxamine interaction was simulated according to different regimens and patient’s characteristics (age and physiological status). The results demonstrated that co-administering salbutamol with fluvoxamine enhanced salbutamol exposure in certain situations, especially when fluvoxamine dosage increased. To sum up, this study demonstrated the utility of PBPK modeling in predicting CYP-mediated DDIs, making it a pioneer in PK DDI research. Furthermore, this study provided insights into the relevance of regular monitoring of patients taking multiple medications, regardless of their characteristics, to prevent adverse outcomes and for the optimization of the therapeutic regimen, in cases where the therapeutic benefit is no longer experienced.