Valproate (VPA)-induced hepatotoxicity is a fatal adverse drug reaction，and children is a high-risk population. Our study aimed to explore whether key genetic polymorphisms of antioxidant pathway is associated with VPA-mediated AST elevation. We included 194 newly diagnosed epilepsy children (aged from 1 to 16 years old) and treated with VPA. These patients were divided into two groups: one group for AST is normal and another group is AST elevated. AST elevation occurred in 25.8% of patient treated with VPA. During VPA monotherapy, the maximum AST in patients of GSTP1 rs1695 with AA genotype was significantly higher than carrying G alleles (36.50 ±14.89 vs 32.88±10.69, P=0.003). Patients with AG+GG genotype of GSTP1 rs1695 had a reduced risk of elevated AST (adjusted OR=0.37, 95% CI: 0.16-0.84, P=0.017). There is a significant difference in the maximum AST value of CAT rs769217 genotype (P=0.011, P= 0.045, respectively). Children with CAT rs769217 CT genotype or CT+TT genotype have a lower risk of elevated AST (adjusted OR=0.30, 95% CI: 0.13-0.68, P=0.004 and adjusted OR=0.41, 95% CI:0.20-0.82,P=0.012, respectively). Children who with GSTP1 rs1695 G allele have a reduced risk of AST abnormalities. We conducted CAT rs769217 CC genotype is a risk factor for AST elevation in children.