AbstractAimsGastrointestinal (GI) dysfunction, as a common peripheral‐organ complication after traumatic brain injury (TBI), is primarily characterized by gut inflammation and damage to the intestinal mucosal barrier (IMB). Previous studies have confirmed that TongQiao HuoXue Decoction (TQHXD) has strong anti‐inflammatory properties and protects against gut injury. However, few have reported on the therapeutic effects of TQHXD in a TBI‐induced GI dysfunction model. We aimed to explore the effects of TQHXD on TBI‐induced GI dysfunction and the underlying mechanism thereof.MethodsWe assessed the protective effects and possible mechanism of TQHXD in treating TBI‐induced GI dysfunction via gene engineering, histological staining, immunofluorescence (IF), 16S ribosomal ribonucleic acid (rRNA) sequencing, real‐time polymerase chain reaction (RT‐PCR), enzyme‐linked immunosorbent assay (ELISA), Western blot (WB), and flow cytometry (FCM).ResultsTQHXD administration ameliorated TBI‐induced GI dysfunction by modulating the abundance and structure of bacteria; reconstructing the destroyed epithelial and chemical barriers of the IMB; and improving M1/M2 macrophage, T‐regulatory cell (Treg)/T helper 1 cell (Th1), as well as Th17/Treg ratios to preserve homeostasis of the intestinal immune barrier. Notably, Cluster of Differentiation 36 (CD36)/15‐lipoxygenase (15‐LO)/nuclear receptor subfamily 4 group A member 1 (NR4A1) signaling was markedly stimulated in colonic tissue of TQHXD‐treated mice. However, insufficiency of both CD36 and (C‐X3‐C motif) chemokine receptor 1 (CX3CR1) worsened GI dysfunction induced by TBI, which could not be rescued by TQHXD.ConclusionTQHXD exerted therapeutic effects on TBI‐induced GI dysfunction by regulating the intestinal biological, chemical, epithelial, and immune barriers of the IMB, and this effect resulted from the stimulation of CD36/NR4A1/15‐LO signaling; however, it could not do so when CX3CR1 and CD36 were deficient. TQHXD might therefore be a potential drug candidate for treating TBI‐induced GI dysfunction.