AimsCefoperazone is commonly used off‐label in the treatment of bacterial meningitis and sepsis in children, and the pharmacokinetic (PK) data are limited in this vulnerable population. The goal of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict pediatric cefoperazone exposure for rational dosing recommendations.MethodsA cefoperazone PBPK model for adults was first constructed using Simcyp V22 simulator. Subsequently, the model was extended to children based on the built in age‐dependent physiological parameters, while the drug characteristics remained unchanged. The verified pediatric PBPK model was then utilized to assess the rationality of the common dosing regimens for children at different age groups.ResultsCefoperazone PBPK model included elimination via biliary excretion, glomerular filtration, and organic anion transporter 3 (OAT3)‐mediated tubular secretion. 95.2% of the observed mean concentrations and 100% of the area under the plasma drug concentration–time curve (AUC) and peak concentration (Cmax) in adults were within a twofold range of model mean predictions. Good predictive accuracy was also observed in children, including neonates. 50 mg/kg q12h cefoperazone demonstrated effective target attainment in virtual term neonates (<1 month) when the MIC was ≤1 mg/L, adhering to the stringent PK/PD target of 75% fT > MIC. 37.5 mg/kg q12h cefoperazone achieved the common 50% fT > MIC target for an MIC ≤ 0. 25 mg/L in virtual pediatric patients ranging from 1 month to 18 years of age.ConclusionsA pediatric PBPK model was developed for cefoperazone, and it could serve as the basis for deriving rational dosing regimens in children.