Central serotonin (5‐hydroxytryptamine, 5‐HT) systems have been implicated in the pathophysiology and treatment of anxiety disorders, which are among the world’s most prevalent psychiatric conditions. Here, we report that the 5‐HT_2C receptor (5‐HT_2CR) subtype is critically involved in regulating behaviors characteristic of anxiety using male 5‐HT_2CR knockout (KO) mice. Specific neural substrates underlying the 5‐HT_2CR KO anxiolytic phenotype were investigated, and we report that 5‐HT_2CR KO mice display a selective blunting of extended amygdala corticotropin‐releasing hormone neuronal activation in response to anxiety stimuli. These findings illustrate a mechanism through which 5‐HT_2CRs affect anxiety‐related behavior and provide insight into the neural circuitry mediating the complex psychological process of anxiety.