Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects multiple brain regions, including the cerebellum. It is characterized by behavioral alterations that significantly impact various aspects of patients' lives. The present study was conducted to examine the anti-inflammatory, antioxidant, and neuromodulatory activities of plumbagin (PLB) in a valproic acid (VPA)-induced autism model. Pregnant rats received an intraperitoneal (i.p.) injection of VPA (600 mg/kg) on day 12.5 of pregnancy. After birth, offspring were orally administered different doses of PLB (0.25, 0.5, and 1 mg/kg) from days 7 to 35. Social interaction and preference were assessed via a three-chamber social assay. Hematoxylin‒eosin (H&E) staining was performed to observe histopathological changes in the cerebellum. Moreover, astrocyte and microglial activation were evaluated by immunostaining. The gene expression levels of Nrf2, HO-1, BDNF, SIRT1, IL-6, IL-1β, TNF-α, and TGF-β1 were evaluated via quantitative real-time PCR (qRT‒PCR). These findings revealed that PLB treatment significantly alleviates social impairments. PLB ameliorated the loss of Purkinje cells and the number of activated astrocytes and microglia in the cerebellum. PLB administration also upregulated the gene expression of Nrf2, HO-1, BDNF, SIRT1, and TGF-β1 and downregulated the IL-6 expression level. Overall, it seems that PLB diminishes autism-related damage in the cerebellum through neuromodulatory activities and attenuation of oxidative stress and inflammation.