Gualou-Xiebai-Banxia decoction (GXB) is one of the famous classical traditional Chinese Medicine (TCM) formula for the treatment of chest stuffiness and pains syndrome in Chinese medicine, i.e., coronary heart disease (CHD) in modern medicine. Being compared with Gualou-Xiebai Baijiu-decoction which only consists of Trichosanthis Pericarpium (TP), Allii Macrostemonis Bulbus (AMB) and wine, GXB is composed of another one additional herbal medicine, Pinellinae Rhizoma Praeparatum (PRP), and is more suitable to treat severe atherosclerosis and dyslipidemia. However, the comprehensive chemical composition of GXB is still unclear, which has seriously hindered the discovery of its effective components for improving the clinical symptoms of CHD. The present study aimed to investigate the overall chemical profile of GXB qualitatively and quantitatively by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS), and further explore the chemical contribution of PRP to this formula combined with chemometric approach. First, a total of 151 components, including steroidal saponins, flavonoids, triterpenoids, nitrogenous and other types components, were detected and characterized by UPLC-Q/TOF-MS in GXB. Then, flavonoids and nitrogenous could be qualitatively observed enrichment in GXB compared to those in GXB-dePRP (GXB deducted PRP in the formula). Furthermore, 19 characteristic components were selected for quantitative comparison between GXB and GXB-dePRP by UPLC-MS/MS combined with chemometric method. These findings indicated that steroidal saponins were the most abundant components in GXB, while the introduction of PRP could not only enrich the structural types of chemical compounds in this formula, but also increase the abundance of active components from other composed herbal medicines, TP and AMB. Taken together, this study developed and validated sensitive and practical methods for qualitative and quantitative analysis of GXB, and clarified the chemical contribution of PRP to this formula. These results laid a solid chemical foundation for further in vivo disposal investigation to screen out the potential effective components as well as therapeutic mechanism research of GXB.