Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy. A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method. The one-compartment model was established to describe the pharmacokinetics of VPA. Twelve single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system and their effects on VPA clearance were evaluated. In the two final popPK models, inclusion of a combined genotype of four variants (rs1042597, rs28365062, rs4986893, and rs4244285), total daily dose (TDD), and body surface area (BSA) significantly reduced inter-individual variability for clearance over the base model. The inter-individual clearance equals to 0.73 x (TDD/628.92)(0.59) x e(UGT-CYP) for TDD included model and 0.70 x (BSA/0.99)(0.57) x e(UGT-CYP) for BSA included model. The precision of all parameters were acceptable (relative standard error < 32.81%). Bootstrap and visual predictive check results indicated that both two final popPK models were stable with acceptable predictive ability. TDD, BSA, and genotype might affect VPA clearance in children. The popPK models may be useful for dosing adjustment in children on VPA therapy.