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Ethnopharmacological relevance: Bu-zhong-yi-qi-tang (BT) is one of a classical formula for descending of spleen-yang, viscerotosis with hyposplenic qi, prolaps of uterus, and prolaps of rectum due to chronic diarrhea in Traditional Chinese Medicine.It has been identified as an effective drug for TCM spleen-qi deficiency pattern in clinical practice.Aim of the study: The present study aimed to investigate the restorative effect and the potential mechanisms of Bu-zhong-yi-qi-tang in rat spleen-qi deficiency model with the 1H-NMR-based metabonomics.Materials and Methods: Rat spleen-qi deficiency model was established according to the following procedure: oral administration of the extract of Rhei Radix (equivalent to crude drug of 10 g/kg body weight), starving for 24 h and heavy loaded swimming every other day.Sixty male SD rats were randomly divided into five groups: a control group not receiving spleen-qi deficiency, a group receiving spleen-qi deficiency, three groups receiving spleen-qi deficiency and a test compound.The aqueous extract of Bu-zhong-yi-qi-tang (equal to the dosage of crude drugs for 5, 10, 20 g/kg body weight) at three doses was administered orally for the last 7 days during the 3 weeks.The body weight and motor behavior were measured and recorded once a week.Endogenous metabolites excreted in plasma were analyzed using NMR in conjunction with multivariate and statistical techniques.In addition, the liver and spleen were removed and weighed.Results: All rats presented a state of pasty loose stools, inactiveness, grouping, swimming endurance drop, fur lackluster, loose and disorderly as well as the significant decrease of body weight, spleen weight and liver weight in spleen-qi deficiency group.While rats in the Bu-zhong-yi-qi-tang-treated groups, the above demonstrations were reversed to a certain extent compared to the model group (p < 0.05, 0.01).Significant separation presented between the control and model groups in PCA score plot, which were an indication that spleen-qi deficiency model was successfully duplicated.The changes of endogenous metabolites in plasma included lower level of valine, leuciure and O-acetyl-glycoprotein as well as higher concentration of lactate in the spleen-qi deficiency group when compared to the control group.The treatment of Bu-zhong-yi-qi-tang could regulate parts of these metabolites to a normal situation.Conclusion: The restorative effects of Bu-zhong-yi-qi-tang on spleen-qi deficiency rats were confirmed and four endogenous metabolites were expected to be the potential biomarkers for spleen-qi deficiency symptoms by intervening in some metabolic pathways, such as energy metabolism, protein metabolism and glycometabolism.