A highly sensitive, specific, and rapid liquid chromatography–tandem mass spectrometry method for determination of lacosamide in human plasma has been developed using lacosamide d6 as an internal standard with 50 µL of human plasma. Protein precipitation technique was used to extract the analyte from human plasma. The chromatographic separation was achieved on ZODIAC C18, 4.6 × 100 mm, 5 µm column using an isocratic mobile phase composition of acetonitrile and 0.1% formic acid buffer (80:20, v/v) at a flow rate of 0.9 mL/min. A detailed method validation was performed as per the recent US FDA guidelines and the calibration curve obtained was linear (r2 = 998) over the concentration range 0.075–25.461 µg/mL. API‐4500 liquid chromatography with tandem mass spectrometry was operated with multiple reaction monitoring mode during the entire analysis. The proposed method was successfully applied to a pharmacokinetic study in healthy, adult human volunteers after oral administration of lacosamide 200 mg film‐coated tablet under fed conditions.