Schizophrenia (SCZ) is a severe, chronic psychiatric illness characterized by delusions and hallucinations, negative symptoms, and cognitive dysfunction that often lead to a lifetime of impairment and disability. Drug development for cognitive dysfunctions of patients with SCZ remains challenging, given the absence of a unifying pathophysiology, and the highly complex underlying genetic architecture. SETD1A, a histone methyltransferase, is a key schizophrenia susceptibility gene. To understand how SETD1A deficiency increases disease risk we employed a mouse model carrying a heterozygous loss-of-function mutation of the orthologous gene. We report that mutant mice exhibit alterations in axonal branching and working memory, as well as a molecular pathology pattern that recapitulates SCZ-related alterations. Notably, restoring Setd1a expression in adulthood rescues working memory deficits. Moreover, we identify demethylases counteracting the effects of Setd1a methyl transferase activity and show that the demethylase antagonism in Setd1a-deficient mice results in a full rescue of the behavioral abnormalities and axonal branching deficits. Our findings advance our understanding of how SETD1A mutations predispose to SCZ and other neurodevelopmental disorders and point to therapeutic interventions.