Introduction: Quaternary alkaloids (QAs) are the major alkaloids in several traditional Chinese medicines, especially in Zanthoxylum simulans. However, few studies on enrichment of QAs from Z. simulans were conducted due to their high polarity and low content. Objective: To develop a weak cation exchange (WCX) solid-phase extraction (SPE) coupled with liquid chromatography mass spectrometry (LC-MS) method to enrich and identify QAs from Z. simulans. Meanwhile, the qualitative and quantitative analyses of QAs were carried out based on the optimum conditions of the method. Methods: Fresh stem bark of Z. simulans was extracted with 70% aqueous methanol and enriched by WCX-SPE. A high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) with an electrospray ionisation (ESI) source was used for the qualitative and quantitative analyses of QAs. Results: Significant improvements were observed in resolution and abundance of the peaks with WCX-SPE. The linearity, limit of detection (LOD) and limit of quantification (LOQ) were determined for this analytical method. The linear relationship (A = 338.85C - 187.72, R² = 0.99) was explored in the range of 0.5 to 312.5 μg/mL for chelerythrine. The LOD and LOQ for chelerythrine standard solutions were 0.0539 mu g/mL and 0.1798 μg/mL, respectively. In addition, 22 peaks were detected successfully with WCX-SPE and nine of them are undetectable without the processing of WCX-SPE. Conclusion: A highly selective and efficient method for simultaneous enrichment and identification of QAs from crude extract of Z. simulans was developed for the first time by combining WCX-SPE with LC-MS.