Background: Saccharum Granorum (YiTang) is a nutrient-rich food that has been used as traditional Chinese medicine (TCM). However, the mechanism responsible for its beneficial efficacy is poorly understood, especially for its roles involved in the TCM formulas. Materials and Methods: In the present work, a classical TCM formulas, Huangqi Jianzhong Tang (HQJZ), was selected to interpret the efficacy and “principal drug” role of YiTang against chronic atrophic gastritis (CAG) rats using a serum metabonomic approach. Results: Twelve candidate metabolites were identified to characterize the difference between CAG and normal rats, which were involved into four disturbed metabolic pathways, including glucose metabolism, amino acid metabolism, fatty acid metabolism, and choline metabolism. The further partial least square regression analysis revealed that five metabolites, including choline, acetate, alanine, a-glucose, and β-glucose, were considered as potential biomarkers related to CAG. YiTang could exert the synergistic effect with HQJZ without YiTang, where the whole formula obtained the best beneficial treatment against metabolic disturbance induced by CAG. The metabolic improvement of YiTang and HQJZ might exert the effects on the dysfunction of energy metabolism, gastric emptying, and the changes of gut microbiome, which were the important pathomechanisms induced by CAG. Conclusion: These findings suggested that YiTang played an indispensable role in HQJZ formula against CAG, which may provide an approach to understand the fundamental idea behind formula construction.