Hypothyroidism is associated with a wide array of medical, neurological, and psychiatric symptoms. Severe hypothyroidism may present as myxedema coma, a medical emergency. In addition, patients may present with myxedema psychosis, a psychiatric emergency manifested as hyperactive encephalopathy, hallucinations, delusions, and suicidal ideation. In rare instances, patients may present with symptoms of mania with psychosis. We present the case of a 26-year-old woman with no known psychiatric history who presented with gradual onset of altered mental status, distractibility, decreased need for sleep, pressured speech, and religious and paranoid delusions. Her medical history was significant for a surgically absent thyroid gland and nonadherence to thyroid hormone. The patient was found to have a severely elevated level of thyroid-stimulating hormone, low level of triiodothyronine, and undetectable thyroxine. Thyroid ultrasound demonstrated a surgically absent thyroid gland. The patient's metabolic panel and random serum cortisol level were normal. Rapid plasma reagin was nonreactive, and toxin screening was negative. It was concluded that severe hypothyroidism was the cause of the patient's mania with psychotic features, given her thyroid hormone levels and lack of history of a psychiatric or substance use disorder. Thyroid hormone monitoring and treatment of hypothyroidism is necessary in all patients who have undergone surgical excision of the thyroid gland. All patients presenting with a first episode mania should be screened for thyroid dysfunction. The preferred treatment includes an atypical antipsychotic and thyroid replacement therapy. Rapid resolution of symptoms can occur with combined levothyroxine and liothyronine. Correction of hypothyroidism improves response to antipsychotics.