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Background and Objectives Prediction of antimicrobial target-site pharmacokinetics is of relevance to optimize treatment with antimicrobial agents. A physiologically based pharmacokinetic (PBPK) model framework was developed for prediction of pulmonary pharmacokinetics, including key pulmonary infection sites (i.e. the alveolar macrophages and the epithelial lining fluid). Methods The modelling framework incorporated three lung PBPK models: a general passive permeability-limited model, a drug-specific permeability-limited model and a quantitative structure–property relationship (QSPR)-informed perfusion-limited model. We applied the modelling framework to three fluoroquinolone antibiotics. Incorporation of experimental drug-specific permeability data was found essential for accurate prediction. Results In the absence of drug-specific transport data, our QSPR-based model has generic applicability. Furthermore, we evaluated the impact of drug properties and pathophysiologically related changes on pulmonary pharmacokinetics. Pulmonary pharmacokinetics were highly affected by physiological changes, causing a shift in the main route of diffusion (i.e. paracellular or transcellular). Finally, we show that lysosomal trapping can cause an overestimation of cytosolic concentrations for basic compounds when measuring drug concentrations in cell homogenate. Conclusion The developed lung PBPK model framework constitutes a promising tool for characterization of pulmonary exposure of systemically administrated antimicrobials. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01186-3.