The quality evaluation of patent drugs derived from traditional Chinese medicine (TCM) compound formulas has been challenging due to their complex chemical composition. In this study, we developed a solution to evaluate the quality of Gegen-Qinlian Decoction (GQD), an ancient four-herb TCM formula for the treatment of diarrhea and diabetes, together with its derived patent drugs by simultaneously quantifying 50 bioactive compounds. The samples were extracted by 100% methanol (for hydrophobic compounds) and 50% methanol in water (for hydrophilic compounds), respectively, and were separated on a Waters Acquity charged surface hybrid C18 column (2.1×100mm, 1.7μm) eluted with gradients of acetonitrile and water containing 0.1% formic acid at a flow rate of 400μL/min. The analytes were determined by ultra-high performance liquid chromatography coupled with tandem mass spectrometry in the selected reaction monitoring mode. The 50 compounds (including acidic and alkaline, hydrophilic and hydrophobic) were well resolved within 14min, and were determined using an internal standard method. The method was fully validated for precision, repeatability, and recovery. The limits of detection were 0.3-10.0ng/mL. Finally, this method was used to analyze 24 batches of GQD samples, including water decoction, pills, tablets, and oral solutions. Principal component analysis indicated significantly varied chemical compositions among these formulations. The tablets and pills contained higher concentrations of Scutellaria and Coptis compounds than the oral solutions, and the water decoction contained abundant glycosides and saponins. Moreover, the contents of flavanones and flavone O-glucuronides varied remarkably. This study provides a feasible solution for the comprehensive quality control of TCM patent drugs.