The simultaneous, quantitative and rapid analysis of plasma concentrations of multiple drugs is important to determine the clinical decision and to expect the prognosis in patients administered in emergency unit with intoxication. Here, we developed the liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based drug screening method for analyzing 12 drugs (acetaminophen, amitriptyline, chlorpromazine, cimetidine, diazepam, doxylamine, ephedrine, imipramine, metoclopramide, propranolol, tramadol, and zolpidem) with frequent events of intoxication throughout the country and evaluated its clinical applicability. The overall sensitivity (low limit of quantitation, $0.1-0.5;{mu}g/mL$), specificity, precision and accuracy for the quantification of 12 drugs were reliable and all drugs can be analyzed within 6 min. Among 12 drugs in samples for quality control, the REMEDi HS-based method detected only 6 drugs with low accuracy, while the LC-MS/MS system was able to precisely quantify all drugs. In addition, pilot analysis of patient samples with unknown drug intoxication was superior to the conventional LC-based drug profiling system, and was rapid and cost effective. In conclusion, LC-MS/MS-based drug screening is a good replacement for conventional LC-based REMEDi analyzer and has the better clinical applicability.