Background: Abdominal pain and constipation are 2 main symptoms in patients with constipation-predominant irritable bowel syndrome (IBS-C). This study aimed to investigate the effects and possible mechanisms of transcutaneous auricular vagal nerve stimulation (taVNS) in patients with IBS-C. Methods: Forty-two patients with IBS-C were randomized into a 4-week sham-taVNS or taVNS treatment. The primary outcomes were complete spontaneous bowel movements per week (CSBMs/week) and visual analog scale (VAS) for abdominal pain. High-resolution anorectal manometry (HRAM) was performed to evaluate anorectal motor and sensory function. Cytokines and brain gut peptides were analyzed in blood samples. ECG was recorded for the assessment of autonomic function. Results: Compared with sham-taVNS, (a) taVNS increased CSBMs/week ( P = 0.001) and decreased VAS pain score ( P = 0.001); (b) improved quality of life ( P = 0.020) and decreased IBS symptom score ( P = 0.001); (c) improved rectoanal inhibitory reflex ( P = 0.014) and improved rectal sensation ( P < 0.04); (d) decreased a number of proinflammatory cytokines and serotonin in circulation; and (e) enhanced vagal activity ( P = 0.040). The vagal activity was weakly correlated with the CSBMs/week ( r = 0.391; P = 0.010) and the VAS pain score ( r = –0.347; P = 0.025). Conclusions: Noninvasive taVNS improves both constipation and abdominal pain in patients with IBS-C. The improvement in IBS-C symptoms might be attributed to the integrative effects of taVNS on intestinal functions mediated via the autoimmune mechanisms. Trial registration: www.chictr.org.cn, no. ChiCTR2000029644. Funding: National Natural Science Foundation of China (grant no. 81970538 for FL).