Abstract Objective To describe the successful use of carbon hemoperfusion and hemodiafiltration in combination with mechanical ventilation (MV) to treat a severe intoxication of 5‐hydroxytryptophan (5‐HTP) in a dog. Case Summary A dog ingested a minimum of 550 mg/kg of extended‐release 5‐HTP, resulting in serotonin syndrome that progressed to a comatose state and severe hypoventilation requiring MV. Extracorporeal carbon hemoperfusion coupled with hemodiafiltration was performed to remove 5‐HTP from this patient. A carbon hemoperfusion cartridge was placed in series upstream in the extracorporeal circuit from the hemodialyzer. A total of 46.5 L of blood (4.89 L/kg) was processed during a 4.85‐hour treatment. Serial plasma samples were obtained at 0, 60, 90, and 150 minutes during the session and 14 hours after the session. These samples were later analyzed for 5‐HTP and serotonin concentrations. The extraction ratio of 5‐HTP was 93.6%–98.9% through the carbon filter. The dog was weaned from MV within 8 hours after extracorporeal therapy and, after a full recovery, was successfully discharged. New or Unique Information Provided Despite an extensive review of the available literature, this appears to be the first reported case of using a carbon hemoperfusion, hemodiafiltration, and MV to treat severe serotonin syndrome secondary to 5‐HTP intoxication in a dog. The combination of carbon hemoperfusion and hemodiafiltration can significantly reduce plasma 5‐HTP concentrations after acute intoxication and may serve to decrease morbidity and mortality in patients with severe intoxication.