To explore the therapeutic role of arginine vasopressin (AVP) and its possible mechanisms in autism.Mid-trimester pregnant rats treated with valproate on embryonic day 12.5 and their offspring were selected as autism model. The autism rats were randomly assigned to autism group and AVP treatment group that given AVP by inhalation per day from postnatal days 21 to 42. The changes in social behavior and the hippocampus transcriptome were compared, and the hub genes were confirmed by quantitative real-time polymerase chain reaction (qPCR) and Mendelian randomization (MR).403 genes were found to be differentially expressed in the autism model, with the majority of these genes being involved in oligodendrocyte development and myelination. Only 11 genes associated with myelination exhibited statistically significant alterations following AVP treatment when compared to the autism group. Gene set enrichment, expression patterns, and weighted gene co-expression network analysis (WGCNA) analysis consistently indicated that the biological processes of oligodendrocyte development and myelination were markedly enriched in the autism group and exhibited improvement following treatment. The variation trend of various nerve cells demonstrated a notable increase in the proportion of oligodendrocytes and oligodendrocyte precursor cells in the autism group, which subsequently exhibited a significant decline following treatment. Five hub genes (MBP, PLIP, CNP, GFAP, and TAOK1) were verified by qPCR. Finally, MR studies have confirmed a causal relationship between hippocampal myelination-related gene expression and the risk of autism.AVP could markedly enhance social interaction abilities in the autism rat model, possibly due to the significantly improved hippocampus oligodendrocytes development and myelination.© 2024 The Author(s). Published by IMR Press.