Licorice is a well-known homologous substance of medicine and food, which has many biological activities, including anti-inflammatory, regulating immunity, etc. According to TCM theory, honey-processed licorice (HPL) is effective in regulating the spleen deficiency syndrome but the mechanism was not clear. In this study, we integrated multi-omics, UHPLC-QTOF-MS and molecular docking to decrypt the metabolic reprogramming mechanism and material basis of HPL in treating spleen deficiency. The main regulated pathway was primary bile acid biosynthesis pathway. The HPL may play a crucial role of anti-spleen deficiency by regulating the content of Taurochenodeoxycholate (TCDCA) to affect the primary bile acid biosynthesis with the content of TCDCA changed significantly according to the results of metabolomic. Furthermore, 70 compounds were identified from HPL using UHPLC-QTOF-MS, among which 18β-glycyrrhetinic, isoliquiritin and liquiritigenin have binding activity with key proteins (CYP7A1, CYP8B1, AKR1D1 and HSD3B7), which may serve as the active ingredients for the intervention of spleen deficiency. Our study demonstrated the potential therapeutic effects of HPL in rats with spleen deficiency, and further investigated the possible material basis and its molecular mechanism. And provide certain experimental basis to clarify the anti-spleen deficiency effect of HPL and the mechanisms involved.