Background: Acute lamotrigine (LTG) overdose can cause refractory cardiac arrhythmias, hypotension, altered mental status, and seizures. Here, we present the case of a patient admitted for massive LTG intoxication refractory to sodium bicarbonate treatment, which improved with lipid rescue therapy. Methods and results: Serum concentrations of therapeutic drugs were measured using liquid chromatography–tandem mass spectrometry. The results showed the LTG level of 63 mg/L. The other quantified drugs were propranolol (441 ng/mL), methylphenidate (0.7 ng/mL), and ritalinic acid (140 ng/mL). The patient developed nonsustained ventricular tachycardia, widening of the QRS complex (up to 160 milliseconds), and unresponsive coma (Glasgow Coma Scale score of 5). The patient was treated with repeated doses of 1 M sodium bicarbonate and other supportive measures. On the fourth day, because of neurological and cardiac refractoriness, a dose of intravenous lipid emulsion (ILE) was administered, resulting in significant improvement in the patient's neurological condition and narrowing of the QRS interval on electrocardiography. The serum LTG concentration was closely monitored over 8 days. The LTG concentration peaked at 127 mg/L from an initial concentration of 63 mg/L, with a half-life (t1/2) of 48.5 hours before ILE administration and 10.5 hours after its administration, determined using a first-order kinetic process. On day 15, the patient was discharged from the intensive care unit. Conclusions: The use of ILE as a rescue option, in addition to other supportive measures, and therapeutic drug monitoring seem to be a reasonable approach, given the patient's refractory response to sodium bicarbonate. Continued research and reporting of such cases will help expand the evidence base and refine management strategies for severe LTG intoxication.