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Pediatric obesity is a growing health concern, affecting millions of children worldwide. While pharmacokinetic (PK) changes in numerous commonly prescribed medications have been linked to obesity, the physiological mechanisms driving these alterations and their implications for drug dosing remain poorly understood. The objective of this study was to evaluate previously reported observations of reduced pantoprazole clearance (CL) in children with obesity, investigate obesity‐related characteristics in liver physiology as explanatory causes for these observations, and evaluate the clinical relevance of obesity on drug dosing. A prospective, comparative PK study, enrolling participants 6‐21 years of age, with and without obesity, was conducted to evaluate the association between obesity‐related characteristics and pantoprazole CL. A nonlinear mixed‐effects modeling approach was used to identify sources of interindividual variability in pantoprazole PK. Monte Carlo simulations were performed to assess pantoprazole exposure in children and evaluate the association between obesity and pantoprazole exposure. The study population consisted of 39 pediatric participants: 31% without obesity and 69% with obesity. A two‐compartment PK model with covariate effects of total body weight (TBW), CYP2C19 metabolizer phenotype, and obesity status adequately described the PK data. After accounting for differences due to TBW and CYP2C19 metabolizer phenotype, obesity was associated with an estimated 18% reduction in pantoprazole CL (comparable to the reduction estimated for a CYP2C19 loss of function allele). Further research is warranted to evaluate the physiological mechanisms associated with reduced drug CL in children with increased body size and the implications for drug dosing. [ABSTRACT FROM AUTHOR]