CONTEXT: L (Rutaceae) (Au) and Blanco (Rutaceae) (Ci) are commonly used as couplet prokinetics and DC. (Umbelliferae) (Bup) is an herbal antidepressant in traditional Chinese medicine. OBJECTIVE: This study evaluates the synergistic prokinetic effects of Bup with Au and Ci in mice suffering from multistress-induced delayed gastric emptying (DGE). MATERIALS AND METHODS: Kunming mice were divided into four groups: control, DGE, AuCi and AuCiBup. Mice were gavaged with AuCi (14.25 g/kg) or AuCiBup (22.13 g/kg) extract for 12 days. Gastric reminder rate, intestinal driving ratio, sucrose preference and open field test were examined, and serotonin (5-HT), motilin (MTL), substance P (SP), 5-HTR and c-kit were assayed. Intracellular Ca levels in primary cultured gastric smooth muscle cells (GSMCs) were determined. RESULTS: Both AuCi and AuCiBup treatment significantly reduced gastric residual rate (39.5% and 67.7%,  < 0.01). Higher serum levels of 5-HT, MTL and SP were observed in treatment groups (AuCi: 0.060 mg/L, AuCiBup: 0.089 mg/L, DGE: 0.025 mg/L,  < 0.01). The expression of 5-HTR and c-kit in the antrum and duodenum was upregulated after treatment (AuCi and AuCiBup, 4.3-times, 2.8-times to DGE,  < 0.01). Medicated serums of AuCi and AuCiBup effectively increased the influx of Ca into GSMCs (1.8-times,  < 0.01). In terms of 5-HTR expression, circulatory contents of 5-HT and SP and Ca influx, AuCiBup demonstrated better prokinetic effects than AuCi. CONCLUSIONS: These findings indicate the potential for developing combination therapy with antidepressants and prokinetics in gastrointestinal dysmotility management.