The Shuang-Huang-Lian (SHL) oral liquid is a combined herbal prescription used in the treatment of acute upper respiratory tract infection, acute bronchitis and pneumonia. Multiple constituents are considered to be responsible for the therapeutic effects of SHL. However, the quantitation of the multi-components from multiple classes is still unsatisfactory because of the high complexity of constituents in SHL. In this study, an accurate, rapid, and specific UPLC-MS/MS method was established for simultaneous quantification of 18 compounds from multiple classes in SHL oral liquid formulations. Chromatographic separation was performed on a HSS T3 (1.8 μm, 2.1 mm × 100 mm) column, using a gradient mobile phase system of 0.1% formic acid in acetonitrile and 0.1% formic acid in water at a flow rate of 0.2 mL·min−1; the run time was 23 min. The MS was operated in negative electrospray ionization (ESI−) for analysis of 18 compounds using multiple reaction monitoring (MRM) mode. UPLC-ESI−-MRM-MS/MS method showed good linear relationships (R2 > 0.999), repeatability (RSD < 3%), precisions (RSD < 3%) and recovery (84.03–101.62%). The validated method was successfully used to determine multiple classes of hydrophilic and lipophilic components in the SHL oral liquids. Finally, principal component analysis (PCA) was used to classify and differentiate SHL oral liquid samples attributed to different manufacturers of China. The proposed UPLC-ESI−-MRM-MS/MS coupled with PCA has been elucidated to be a simple and reliable method for quality evaluation of SHL oral liquids.