<h3>Purpose/Objective(s)</h3> Cancer-related fatigue (CRF) is the most common symptom in breast cancer patients treated with radiotherapy (RT). Acupuncture was reported to be effective in the management of CRF due to enhanced vagus nerve activity and improved lymphopenia. We hypothesized that transcutaneous vagal nerve stimulation (tVNS) is effective for CRF in a more convenient and non-invasive way. <h3>Materials/Methods</h3> From April 2020 to December 2021, a total of 247 breast cancer patients receiving RT to the breast/chest wall ± regional lymph nodes were included in this study. Patients were randomized 2:1 to the tVNS group (n=163) or the sham tVNS group (stVNS group, n=84). The electrode clip was placed on the tragus with power on or off, once daily throughout RT. Both the patient and the assessing physician were blinded to the assignment. The primary endpoint was improvement of CRF in one month after RT (measured by the Brief Fatigue Inventory, BFI) and the change of lymphocytes during RT. Secondary endpoint included anxiety and depression (measured by Hospital Anxiety and Depression Scale, HADS), the sleep dysfunction (measured by Pittsburgh Sleep Quality Index, PSQI), and quality of life (measured by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire, EORTC QLQ-C30). ClinicalTrials.gov Identifier: NCT04563013. <h3>Results</h3> Baseline characteristics were well balanced between the two groups. In CRF improvement, the median (quartile) of BFI total score and comprehensive fatigue effect score of tVNS group was significantly lower than that in stVNS group (1.0 [0.3, 2.2] vs 1.7 [0.7, 3.6], <i>p</i>=0.015; 0.8 [0, 1.6] vs 1.4 [0.7, 3.8], <i>p</i>=0.005, respectively). The change in lymphocytes of tVNS group were significantly less than that in stVNS group from baseline to week 4 (median, -0.8 × 10<sup>9</sup>/L vs -1.0 × 10<sup>9</sup>/L, <i>p</i>=0.014), and to the end of RT (median, -0.9 × 10<sup>9</sup>/L vs -1.0 × 10<sup>9</sup>/L, <i>p</i>=0.004). In terms of psychological status, tVNS significantly lowered the total score (median, 3.0 vs 7.0, <i>p</i>=0.012) and the depression score (median, 1.0 vs 3.0, <i>p</i>=0.005) of HADS one month after RT. No significant difference in anxiety scores between the two groups (median, 2.0 vs 4.0, <i>p</i>=0.085). Patients in tVNS group had less sleep latency (median scores, 1.0 vs 2.0, <i>p</i>=0.042) and better social functioning (median scores, 100.0 vs 83.3, <i>p</i>=0.020) than stVNS group in one month after RT. No ear irritation or obvious changes in the external skin were observed. <h3>Conclusion</h3> tVNS can significantly improve the CRF, lymphopenia, and quality of life in breast cancer patients receiving RT.