Longhu Rendan pills (LRPs) are one of the most widely used traditional Chinese over-the-counter medicines for the prevention and treatment of heat stroke and motion sickness. A rapid and effective GC-MS/MS method for the determination of six volatile active constituents including menthol, borneol, isoborneol, anethole, eugenol and acetyl eugenol in LRPs was developed and validated. The six compounds were separated within 8 min using a VF-WAXms capillary column, and the analytes were quantified using GC-MS/MS in multiple reaction monitoring mode. Good linearity was achieved (r > 0.9973). Variations in the intra- and inter-day precisions of all the analytes were below 4.32%, and the accuracy (92.44% to 103.64%) was evaluated using a recovery test. The method successfully determined six volatile compounds in three batches of LRP samples. The present study offers a highly accurate, sensitive and reliable method for the determination of six volatile active constituents in LRPs to promote the quality control investigation of LRPs.