Contradictory pharmacokinetic (PK) results have been observed between obese adults and obese adolescents, with absolute clearance (CL) reported to be either unaltered, lower, or higher in obese adolescents compared to obese adults. This study investigates the PK of vancomycin in adolescents and adults who are overweight or obese. Data from 125 overweight and obese adolescents (aged 10-18 years, weight 28.3-188 kg) and 81 overweight and obese adults (aged 29-88 years, weight 66.7-143 kg) were analysed using population PK modelling. In addition to age, sex, renal function estimates, and regular weight descriptors, we evaluated standard weight (WTstandard, defined as weight for length, age, and sex in adolescents and weight for length in adults) and excess weight (WTexcess, defined as total body weight (TBW) minus WTstandard) as covariates in order to distinguish between weight resulting from length versus weight resulting from obesity. Analyzing adolescents and adults together, vancomycin CL was found to increase with TBW and decrease with increasing age (p < 0.001). A covariate analysis investigating adolescents and adults separately found that vancomycin CL increased with WTstandard in adolescents and adults, albeit with different functions, with adolescents having a higher CL per WTstandard than adults. Moreover, in this separate model, adolescent males had 21% higher CL than adolescent females of the same WTstandard, while in adults, CL decreased with increasing age (p < 0.001). There are apparent differences in vancomycin CL in overweight and obese adults versus overweight and obese adolescents, implying that dosing of vancomycin cannot be directly extrapolated between these populations.