Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and impact disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in nine patients with intellectual disability, seizures, autism, dysmorphisms and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least two of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies nine individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy and other developmental anomalies.