Serotonin 2A receptors (5-HT(2A)Rs) mediate the hallucinogenic effects of psychedelic drugs and are a key target of the leading class of medications used to treat psychotic disorders. These findings suggest that dysfunction of 5-HT(2A)Rs may contribute to the symptoms of schizophrenia, a mental illness characterized by perceptual and cognitive disturbances. Indeed, numerous studies have found that 5-HT(2A)Rs are reduced in the brains of individuals with schizophrenia. However, the mechanisms that regulate 5-HT2AR expression remain poorly understood. Here, we show that a physiologic environmental stimulus, sleep deprivation, significantly upregulates 5-HT2AR levels in the mouse frontal cortex in as little as 6-8 h (for mRNA and protein, respectively). This induction requires the activity-dependent immediate early gene transcription factor early growth response 3 (Egr3) as it does not occur in Egr3 deficient (-/-) mice. Using chromatin immunoprecipitation, we show that EGR3 protein binds to the promoter of Htr2a, the gene that encodes the 5-HT2AR, in the frontal cortex in vivo, and drives expression of in vitro reporter constructs via two EGR3 binding sites in the Htr2a promoter. These results suggest that EGR3 directly regulates Htr2a expression, and 5-HT2AR levels, in the frontal cortex in response to physiologic stimuli. Analysis of publicly available post-mortem gene expression data revealed that both EGR3 and HTR2A mRNA are reduced in the prefrontal cortex of schizophrenia patients compared to controls. Together these findings suggest a mechanism by which environmental stimuli alter levels of a brain receptor that may mediate the symptoms, and treatment, of mental illness.