Since its initial description more than 70 years ago, autism spectrum disorder (ASD) has been diagnosed more frequently in boys. However, we remain unsure of why males are affected in greater numbers. Genetic and hormonal causes have been proposed, but clinicians and researchers are still debating whether males are more susceptible or females are more resilient. One primary hurdle in testing different hypotheses was the lack of appropriate animal models. In developing a novel mouse model of ASD and intellectual disability (ID) lacking Coiled-coil and C2 domain containing 1a, CC2D1A, which is mutated in humans with ID, ASD and seizures, we found that male mice are more severely affected than females. While males show an array of memory and sociability deficits with hyperactivity and anxiety, females only display a subset of learning impairments. In parallel, sex-specific behavioral differences correlate with male-specific reduction in activation of the transcription factor CREB in the hippocampus of KO animals. CREB function is critical for spatial memory formation, and modulation of CREB signaling rescues both molecular and behavioral deficits in male KO mice. Our results indicate that CC2D1A may establish male-specific signaling processes controlling memory. Defining how male-specific signaling is established will provide key insight on sex specific signaling in the brain, and will also lead to significant advances in the understanding of mechanisms that could lead to male bias in neurodevelopmental disorders.