Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by repeated rising thoughts and repetitive unwanted behaviors. Selective serotonin reuptake inhibitors (SSRIs) are widely used as the first-choice treatment for OCD. Previously, we reported that mice received repeated injections of quinpirole (QNP; a dopamine D₂ receptor agonist; 1 mg/kg; 8 days) displayed OCD-like abnormalities, which were ameliorated by chronic SSRI administration. In this study, we aimed to investigate therapeutic mechanisms of SSRI for OCD. In acute brain slices from QNP-treated mice, chronic administration of an SSRI (citalopram; 24 mg/kg/day, 28 days) ameliorated hyperactivity of pyramidal neurons in the lateral orbitofrontal cortex (lOFC). SSRI administration increased the frequency of inhibitory inputs to lOFC pyramidal neurons. These effects of SSRI were mimicked by acute perfusion of SB242084 (a 5-HT_2c receptor antagonist; 3 μM). In contrast, SB242084 attenuated inhibitory inputs to lOFC fast-spiking interneurons, suggesting that 5-HT2c receptor antagonism inhibits lOFC pyramidal neurons by disinhibition of local fast-spiking interneurons. Consistent with electrophysiological experiments, short-term administration of SB242084 (1 mg/kg) improved reversal learning deficit in QNP-treated mice. These results revealed that chronic SSRI treatment improved OCD-like abnormalities through attenuation of 5-HT_2c receptor signaling in the lOFC, indicating a potential of 5-HT_2c receptor inhibition as a new therapeutic target for OCD.