Abstract Because of its involvement in breathing control and neuronal excitability, dysregulation of the serotonin (5‐HT) 2C receptor (5‐HT2C) might play a key role in sudden unexpected death in epilepsy. Seizure‐induced respiratory arrest is thus prevented by a 5‐HT2B/C agonist in different seizure model. However, the specific contribution of 5‐HT2C in chronic epilepsy‐related respiratory dysfunction remains unknown. In a rat model of temporal lobe epilepsy (EPI rats), in which we previously reported interictal respiratory dysfunctions and a reduction of brainstem 5‐HT tone, quantitative reverse transcriptase polymerase chain reaction showed overexpression of TPH2 (5‐HT synthesis enzyme), SERT (5‐HT reuptake transporter), and 5‐HT2C transcript levels in the brainstem of EPI rats, and of RNA‐specific adenosine deaminase (ADAR1, ADAR2) involved in the production of 5‐HT2C isoforms. Interictal ventilation was assessed with whole‐body plethysmography before and 2 h after administration of SB242084 (2 mg/kg), a specific antagonist of 5‐HT2C. As expected, SB242084 administration induced a progressive decrease in ventilatory parameters and an alteration of breathing stability in both control and EPI rats. However, the size of the SB242084 effect was lower in EPI rats than in controls. Increased 5‐HT2C gene expression in the brainstem of EPI rats could be part of a compensatory mechanism against epilepsy‐related low 5‐HT tone and expression of 5‐HT2C isoforms for which 5‐HT affinity might be lower.