Huangqi Guizhi Wuwu Decoction (HGWD), a famous Chinese medicine prescription, has been widely used in the treatment of diabetic peripheral neuropathy and scleroderma in China. Considering that the decoction was not easy to store and carry, our research group has converted HGWD into Huangqi Guizhi Wuwu Granules (HGWG) in the early stage. However, the in vivo metabolism profile of HGWG was still unclear. In this study, an ultra–high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) method was established to identify prototypes and metabolites in urine and feces of rats after oral administration of HGWG. A total of 100 compounds were identified in urine and feces samples. In the urine samples, 28 prototype compounds and 41 related metabolites were identified. In the feces samples, 39 prototype compounds and 12 related metabolites were identified. Monoterpenoid glucosides, flavonoids, organic acids, gingerols, and terpenes were the main prototype compounds in both rat urine and feces. Flavonoid-related metabolites, organic acid-related metabolites, and gingerol-related metabolites were the major metabolites in rat urine, and flavonoid-related metabolites were the major metabolites in rat feces. This study can provide a theoretical basis for the drug metabolism and new drug development research of HGWG.