Loss of function mutations in genes encoding lysine methyltransferases responsible for trimethylation of histone 3 on lysine 4 (H3K4me3) are associated with a range of neurodevelopmental conditions. Intriguingly, mutations of H3K4me3-specific lysine demethylases (KDMs) are also associated with autism and intellectual disability. Mutations in KDM5B have been reported in patients with autism, intellectual disability and developmental delay. We hypothesised that a deficiency in the demethylation activity of KDM5B will lead to a dysregulated H3K4me3 epigenome, abnormal neurodevelopmental gene expression and autism-like behaviours in mice. As KDMs have multiple mechanistic functions, we studied neurodevelopmental phenotypes in mice that specifically lack KDM5B demethylase activity to determine the role of H3K4me3 demethylation in brain development. These mice exhibited autism-like behaviours, which included socio-communication deficits and repetitive behaviours. Brain growth was increased relative to other organs and magnetic resonance imaging (MRI) revealed increased brain size, encompassing both grey and white matter in adult mice. H3K4me3 levels were significantly elevated in the postnatal neocortex, indicating that KDM5B functions as a H3K4me3 demethylase in the developing brain. RNA-seq analyses identified abnormal expression of many neurodevelopmental genes, including upregulation of the NMDAR subunit gene, Grin2d. Treatment of Kdm5b-deficient mice with the NMDAR antagonist, memantine, restored abnormal ultrasonic vocalisations in pups and reduced repetitive digging behaviours in adult mice. These findings suggest that increased H3K4me3 levels and associated Grin2d gene upregulation disrupt brain development and function, leading to socio-communication deficits and repetitive behaviours, and identify a potential treatment for autism-like behavioural phenotypes associated with KDM5B deficiency.