Toxic megacolon is a potentially lethal disease process in which there is a non-mechanical dilation of the colon to >6 cm, often associated with systemic effects including leukocytosis or hemodynamic compromise. Here, we present a case of a 49-year-old male who presented with idiopathic toxic megacolon who underwent a subtotal colectomy with end ileostomy. Pathology confirmed no inflammatory bowel disease or Clostridium difficile infection, the most common etiologies. This was a unique case in that the patient did not present with the most common etiology, but did have a history of chronic constipation in the setting of antipsychotic/antidepressant use. Scattered cases of antipsychotic-induced toxic megacolon have been described in the literature, but to the author's knowledge, none related to aripiprazole or clomipramine. This case highlights the importance of diligent clinical monitoring for patients on psychiatric medications.