Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental conditions, the etiology of which remains elusive. Sialic acid (SA) is an essential nutrient for nervous system development, and previous studies reported that the levels of SA were decreased in the blood and saliva of ASD children. However, it is not clear whether SA supplementation can alleviate behavioral problems in autism. We administered SA intervention in the VPA-induced autism model rats, evaluated behavior performance, and measured the levels of Gne and St8sia2 genes, BDNF and anti-GM1. At the same time, untargeted metabolomics was used to characterize the metabolites. It was found that the stereotypical behaviors, social preference and cognitive function were improved after SA supplementation. Additionally, the number of hippocampal neurons was increased, and the shape was normalized. Moreover, 94 differentially abundant metabolites were identified between the high dose SA and VPA groups. These changes in metabolites were correlated with pyrimidine metabolism, lysine degradation metabolism, biosynthesis of amino acids, mineral absorption, protein digestion and absorption, galactose metabolism, phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism. In conclusion, SA could ameliorate ASD-like phenotypes and change metabolites in autistic animals, which suggests that it may be a therapeutic approach for ASD.