Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disability that demonstrates impaired social interactions, communication deficits, and restrictive and repetitive behaviors. ASD has a strong genetic basis and many ASD-associated genes have been discovered thus far. Our previous work has shown that loss of expression of the X-linked gene is implicated in patients with autistic features and intellectual disability (ID). To further determine the causal role of the gene in the disorder, and to understand the cellular and molecular mechanisms underlying the pathology, we have generated a NEXMIF knock-out (KO) mouse. We find that male NEXMIF KO mice demonstrate reduced sociability and communication, elevated repetitive grooming behavior, and deficits in learning and memory. Loss of expression results in a significant decrease in synapse density and synaptic protein expression. Consistently, male KO animals show aberrant synaptic function as measured by excitatory miniatures and postsynaptic currents in the hippocampus. These findings indicate that NEXMIF KO mice recapitulate the phenotypes of the human disorder. The NEXMIF KO mouse model will be a valuable tool for studying the complex mechanisms involved in ASD and for the development of novel therapeutics for this disorder. Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by behavioral phenotypes. Based on our previous work, which indicated the loss of NEXMIF/KIDLIA was associated with ASD, we generated NEXMIF knock-out (KO) mice. The NEXMIF KO mice demonstrate autism-like behaviors including deficits in social interaction, increased repetitive self-grooming, and impairments in communication and in learning and memory. The KO neurons show reduced synapse density and a suppression in synaptic transmission, indicating a role for NEXMIF in regulating synapse development and function. The NEXMIF KO mouse faithfully recapitulates the human disorder, and thus serves as an animal model for future investigation of the NEXMIF-dependent neurodevelopmental disorders.