Autism spectrum disorder (ASD) describes a heterogeneous group of neurodevelopmental conditions characterized by deficits in social communication and repetitive behaviors. Aripiprazole (APZ) is an atypical antipsychotic that can safeguard mice against autism-like behavior induced by valproic acid (VPA). In the present study, we examined the effects of maternal treatment with APZ (10 mg/kg) in juvenile mice prenatally exposed to VPA on neurodevelopmental behaviors, social interactions, communication, and working memory, as well as synaptophysin (SYP), synaptosomal-associated protein, 25 kDa (SNAP-25) and microtubule-associated protein 2 (MAP-2) expression in the medial prefrontal cortex (mPFC) and cell viability in the hippocampus. In addition, to evaluate possible APZ interference with the anticonvulsant properties of VPA on pentylenetetrazole (PTZ)-induced seizures were evaluated. Maternal treatment with APZ significantly prevented body weight loss, self-righting, eye-opening, social interactions, social communication, and working memory deficits in mice prenatally exposed to VPA. Additionally, the decrease in the SYP, SNAP-25, and MAP-2 expressions in the mPFC and cell death in the hippocampus was prevented by APZ. Furthermore, APZ (10 mg/kg) did not interfere with the anticonvulsant effect of VPA (15 mg/kg) in animals with PTZ-induced seizures. These findings indicate that maternal treatment with APZ in pregnant mice exposed to VPA protects animals against the ASD-like behavioral phenotype, and this effect may be related, at least in part, to synaptic plasticity and neuronal protection in the PFC and hippocampus. APZ may serve as an effective pharmacological therapeutic target against autistic behaviors in the VPA animal model of ASD, which should be further investigated to verify its clinical relevance.