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Valproic acid is a broad-spectrum anticonvulsant medication that is used to treat multiple neurologic and psychiatric disorders such as epilepsy, bipolar disorder, schizophrenia, and migraine prophylaxis. Famotidine is an antacid used for various gastrointestinal conditions, including gastric and duodenal ulcers and gastroesophageal acid reflux disease (GERD). Acute ingestion of famotidine was found to inhibit anticonvulsant action and increase brain concentrations relative to free plasma levels in a mouse model. While they are not known to interact with one another, one of their proposed metabolisms is through the same CYP450 enzyme. However, a drug-drug interaction between valproic acid and famotidine, or this interaction causing toxicity in a child, is extremely rare. A 10-year-old male with a past medical history of bipolar disorder, posttraumatic stress disorder, and anxiety presented to a community emergency department (ED) with acute altered mental status and increasing somnolence. Routinely taking valproic acid, he had started prescription famotidine two days prior. In the ED, his valproic acid levels were six times the upper limit of normal with associated elevated creatinine and hypocalcemia. Later, hyperammonemia developed. He was ultimately treated with L-carnitine, lactulose, and meropenem as well as admitted to the pediatric intensive care unit (PICU) with normalization of lab values and complete resolution of his neurologic symptoms after 29 hours. This case describes an extremely rare drug-to-drug interaction of valproic acid and famotidine leading to acute altered mental status in a pediatric patient. While causality cannot be established from a single case, clinicians should consider this potential interaction when new medications are added to a stable valproic acid regimen, as these two medications are commonly prescribed in both adults and children.