The 22q11.2 deletion syndrome (22q11DS) is a genetic disorder characterized by defined microdeletions at chromosome 22q11.2. These genetic changes lead to a variety of neurodevelopmental problems, including cognitive delays and a very high rate of symptoms on the autism and schizophrenia spectrum. The underlying mechanisms contributing to these neurodevelopmental manifestations remain poorly understood. In concert with these neurodevelopmental difficulties there are also immune system alterations, including autoimmunity. We hypothesize that immune dysfunction, and the presence of circulating autoantibodies may play a role in the pathophysiology of these neuropsychiatric symptoms. In this review, we synthesize the diverse literature on autoantibodies in 22q11DS and propose mechanisms for a causative role of these autoantibodies in neurobehavioral problems such as psychosis and cognitive delays. This review highlights the importance of further research to explore the interaction between autoreactive antibodies and functional alterations in neurocircuitry function. Understanding this relationship may provide insight into the origins of psychiatric symptoms.