In this paper, the authors proposed a simple, rapid and highly sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method for the determination of riluzole in human plasma. Carbamazepine was used as an internal standard (IS). The method employed only 100 μL of human plasma for sample processing by a simple protein precipitation technique. The processed samples were chromatographed on a C₁₈ column by using a mixture of 0.1% formic acid–acetonitrile (30 : 70, v/v) as the mobile phase at a flow rate of 0.9 mL min⁻¹. The calibration curve obtained was linear over the concentration range of 0.10–500 ng mL⁻¹ with r² ≥ 0.99. Method validation was performed as per the FDA guidelines and the results met the acceptance criteria. The multiple reaction-monitoring mode (MRM) was used for quantification of ion transitions at m/z 235.0/165.9 and 237.2/194.1 for the analyte and the IS, respectively. A run time of 2.0 min for each sample made it possible to analyze more than 400 plasma samples per day, thus increasing the productivity. The validated method was successfully applied to a clinical pharmacokinetic study in South Indian male subjects under fasting conditions with a 50 mg riluzole tablet.