Patients with a spleen-qi deficiency often exhibit dysfunction in the metabolic system. Metabolites are considered the most direct reflection of individual physiological and pathological conditions and represent attractive candidates to provide deep insights into disease phenotypes. This study examines the potential therapeutic mechanism of wild ginseng on spleen-qi deficiency through the analysis of serum and urine metabolomics using rapid-resolution liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. The reasons for the superiority of wild ginseng treatment over cultivated ginseng were also analyzed in depth. After wild ginseng intervention, anandamide, urobilinogen, aldosterone, and testosterone glucuronide were significantly reduced in serum. Meanwhile, argininosuccinic acid, L-cysteine, and seven other metabolites were significantly elevated in serum. Nine metabolites, including Lacetylcarnitine, and citrulline were elevated in the urine, and trimethylamine N-oxide, adrenic acid, and 10 other metabolites were reduced. Arginine biosynthesis, pantothenate and CoA biosynthesis, thiamin metabolism, taurine, and tryptophan metabolism pathways were mainly improved. Further analysis was conducted on the relationship between Lactobacillus and Akkermansia bacteria with metabolites, and it was found that they are mainly related to amino acid metabolites. This study provides strong theoretical support and direction for further explanation of the immune mechanism of wild ginseng and lays the foundation for future studies.