BACKGROUND: Gastrointestinal (GI) motility disorders affect a large proportion of the population with limited treatment options. The aims of this study were to investigate the potential of a non-invasive method of auricular vagal nerve stimulation (aVNS) for treating GI dysmotility and to explore possible mechanisms involving slow waves and interstitial cells of Cajal (ICC). METHODS: Normal rats were treated daily with loperamide for 1 week and then treated, while still on daily loperamide, with aVNS/Sham-aVNS for another 1 week. Gastric emptying (GE), small intestine transit (SIT), and GI slow waves were measured. The plasma level of pancreatic polypeptide (PP) and noradrenaline (NE) was assessed by ELISA. ICC in the gastric antrum were detected by immunohistochemistry. KEY RESULTS: (a) aVNS significantly increased the percentage of normal GI slow waves (p < 0.05 for both fasting and postprandial states, vs. Sham-aVNS) and accelerated GE (p < 0.05, vs. Sham-aVNS) and SIT (p < 0.05, vs. Sham-aVNS) impaired by loperamide. (b) aVNS increased plasma PP (p < 0.01) and decreased plasma NE (p < 0.01), compared with Sham-aVNS. (c) Gastric ICC was decreased by loperamide (p < 0.01) but increased after aVNS (p < 0.01, vs. Sham aVNS). CONCLUSIONS & INFERENCES: Loperamide induces upper GI dysmotility. aVNS accelerates upper GI transit and improving pace-making activity mediated via the ICC. Non-invasive aVNS may have a therapeutic potential for upper GI dysmotility.