This study explores the link between Autism Spectrum Disorder (ASD) and the transcriptional factor zinc finger and BTB domain-containing protein 20 (ZBTB20), known for its role in Primrose syndrome and ASD. We used a ZBTB20 haploinsufficient mouse model to demonstrate an autism-like phenotype, including impaired sociability, reduced vocalization, repetitive behavior, cognitive inflexibility, hyperactivity, and reduced sensitivity to pain. For the first time, MRI scans were conducted in an animal model, revealing structural changes in the brain, specifically in the hippocampus and cerebellum. In a previous study, we found that treatment with recombinant human erythropoietin (rhEPO) increased ZBTB20 expression in pyramidal neurons, suggesting that rhEPO could enhance residual expression in ZBTB20 deficient mice, thus alleviating the behavioral phenotype. Our results show that rhEPO improves sociability, cognitive flexibility, working memory, and exploratory motivation in ZBTB20 deficient mice. While no significant changes were observed in fluorescence-activated cell sorting, snRNA sequencing showed the impact of rhEPO on pyramidal neuron expression. In conclusion, our study emphasizes the utility of ZBTB20+/- mice as a model for ASD research, particularly in the context of Primrose syndrome, and suggests rhEPO as a potential treatment for mitigating autism-like symptoms in ZBTB20 deficient mice.