Objective To observe the efficacy of Jieyu Fuwei Powder in the treatment of patients with functional dyspepsia (FD). Methods A total of 66 patients with chronic FD (type of disharmony between liver and stomach) from the outpatient clinic of Hai'an Hospital of Traditional Chinese Medicine were randomly divided into two groups, with 33 cases in each group. Control group was treated with domperidone, while treatment group was treated with Jieyu Fuwei Powder. The total effective rate, scores of traditional Chinese medicine syndromes, levels of serum 5-hydroxytryptamine (5-HT), substance P (SP), gastrin (GAS) and motilin (MTL) as well as the incidence of adverse reactions were compared between the two groups. Volunteers from the two groups after treatment (14 cases in the control group and 13 cases in the treatment group) were recruited to receive outpatient gastroscopy and obtain biopsy tissues for histopathological and immunohistochemical analysis of GAS and MTL. Results The total effective rate in the treatment group was 90.91%, which was significantly higher than 69.70% in the control group (P < 0.05). After treatment, the scores of symptoms such as pain in both sides of the chest, epigastric fullness, upper abdominal discomfort, belching, heartburn and irritability in the treatment group were significantly lower than those in the control group (P < 0.01). After treatment, the levels of serum 5-HT and SP decreased significantly while the levels of MTL and GAS increased significantly in both groups, and the levels of serum 5-HT and SP were significantly lower in the treatment group than those in the control group, while the levels of MTL and GAS were significantly higher in the treatment group than those in the control group (P < 0.05 orP < 0.01). The incidence of adverse reactions was 6.06% (2/33) in the treatment group and 9.09% (3/33) in the control group, with no significant difference between two groups (P>0.05). Hematoxylin an eosin (HE) staining of biopsy tissues showed no significant difference in pathology between the two groups, and immunohistochemical results suggested that the expression level of GAS and MTL in the treatment group was higher than that in the control group. Conclusion Efficacy of Jieyu Fuwei Powder in the treatment of FD differentiated as type of disharmony between liver and stomach is superior to domperidone, and its mechanism may be related to the intervention of brain-gut interaction.