Valproic acid (VPA) is a potent inducer of neural tube defects in human and mouse, its teratogenicity is associated with its potential to generation of free radicals and increase oxidative stress. Furthermore, spirulina (SP) has shown pharmacological properties against teratogenicity, which are attributed to its antioxidant potential. Accordingly, the present study was performed to investigate the influence of SP on the teratogenicity of VPA in imprinting control region mice and the possible mechanisms of action. VPA (sodium valproate) was administered intraperitoneally to mice on gestation day (GD) 8 at a dose of 600 mg/kg. SP was given orally at 125, 250, and 500 mg/kg daily from GD0 through GD18. The most common finding in fetuses with VPA exposure was exencephaly. SP decreased the incidence of this and other malformations and increased levels of superoxide dismutase, catalase, and glutathione peroxidase. In conclusion, these results illustrate the protective action of SP through its antioxidant activity against VPA-induced teratogenicity.