Antiepileptic drugs (AEDs) have been used to control epilepsy. More than 17 new AEDs, including gabapentin (GPN), lacosamide (LCM), perampanel (PER), pregabalin (PRG), rufinamide (RFM), and vigabatrin (VGB) have been approved and marketed since 1989. Accurate measurement of serum concentration of the antiepileptic drugs is crucial to achieve optimal efficacy and avoid adverse events. We describe an accurate and precise liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of GPN, LCM, PER, PRG, RFM, and VGB in serum. The method requires a small volume of sample (10 μL) and has a total chromatographic run time of 4 min for simultaneous measurement of these drugs. The method showed good accuracy with a bias of -0.2-5%. The intra- and inter-day imprecision were less than 5.0% for all the analytes. The linear assay ranges were 0.3-26 μg/mL for GPN, 0.15-24 μg/mL for LCM, 7.4-1881 ng/mL for PER, 0.03-13 μg/mL for PRG, 0.78-90 μg/mL for RFM, and 0.3-43 μg/mL for VGB.