A method for determining eight water-soluble impurities in medicinal composite packaging bag by HPLC-MS/MS simultaneously was established. The medicinal composite packaging bag was cut into small pieces and then extracted by ultrapure water with ultrasonic wave at 50 ℃ for 30 min, followed by clean-up through a 0.22 μm polytetrafluoroethylene (PTFE) membrane. The separation was conducted on ZORBAX Eclipse XDB-C₁₈ (3.5 μm, 4.6 mm×150.0 mm) with methanol-0.1% formic acid as mobile phase. The target compounds were detected under electrospray ionization (ESI) positive ion multiple reactive monitoring (MRM) mode, and quantified by external standard method. The chromatographic column, mobile phase and mass spectrum parameters were optimized, and the matrix effect was assessed. The results showed that the limits of determination (LOD) were 0.20~0.35 ng/g, the linear correlation coefficients were all higher than 0.995, the average recoveries were 85.0%~115.8%, and the RSD were 0.3%~9.2% (n=6) under the optimized conditions. The method exhibited the advantages of simple pretreatment, short analysis time (6 min) and slight matrix effect, which can be used for the rapid screening of eight water-soluble impurities in medicinal composite packaging bag.