Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including Nrg1 (neuregulin 1) and Akt1 (PKBα). Recent findings also revealed that Nrg1 acts through ErbB2/4 in a paracrine fashion to stimulate the PI3-kinase/Akt signaling pathway, which might be involved in the functional outcomes of schizophrenic patients. Taking advantage of genetically modified mice as a model, we aim to investigate the impact of gene-gene interaction in the regulation of schizophrenia-related behavioral phenotypes. In this study, both Akt1 and Nrg1 single and double mutant mice and their wild-type littermates were used to examine the effect of these genes on behavioral and social cognitive phenotypes. In experiment 1, double mutant mice displayed a normal profile of body weight and brain activity. In experiment 2, no significant group differences were found in our basic behavioral battery, including locomotion, anxiety-like behavior, and sensorimotor gating. However, both double mutant mice and Nrg1-/+ mice exhibited an impairment of episodic-like memory. Double mutant mice also had impaired sociability. In experiment 3, we further examined the social communication of double mutant mice and found that they spent less time investigating estrus female, male, and ovariectomized mice. They also emitted fewer female urine-induced ultrasonic vocalization calls compared to the other three groups. Collectively, our results indicate that double deficiency of Nrg1 and Akt1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition.