OBJECTIVE: Cancer-related fatigue (CRF) is a well-recognized issue for cancer patients undergoing chemotherapy; however, research on nonpharmacological alternatives have been underreported. This study is aimed at investigating the effect of mild moxibustion on CRF in patients with non-small-cell lung cancer (NSCLC) undergoing chemotherapy. METHODS: A randomized controlled trial was performed on 126 NSCLC patients undergoing initial chemotherapy and were divided into the following three groups: mild moxibustion group, sham acupoint group, and control group. Moxibustion was performed on two groups of acupuncture points, Dazhui and Geshu acupoints in the prone position and Qihai, Guanyuan, and Zusanli acupoints in the supine position, during the chemotherapy for 30 min with one of the groups of acupuncture points per day. Moxibustion of the sham group was performed 1 cm away from the true acupoint, while only routine nursing care was given to the routine group. The efficacy and safety of the treatments were assessed based on the Chinese version of the Revised Piper Fatigue Scale (RPFS-CV), the quality of life (QoL) questionnaire for Chinese cancer patients receiving chemobiotherapy (QLQ-CCC), and liver and kidney function indexes. RESULTS: A total of 118 cases completed all interventions. There was no significant difference in the baseline indicators among the three groups of NSCLC patients. Although all three groups demonstrated raised RPFS-CV scores over the chemotherapy cycle, comparatively, the mild moxibustion group had significantly lower RPFS-CV scores and better relief of CRF symptoms ( < 0.05). The QLQ-CCC results indicated that the QoL of NSCLC patients dramatically decreased following chemotherapy, even with mild moxibustion. Further, mild moxibustion intervention did not show significantly different levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Scr), and blood urea nitrogen (BUN) compared with the two other groups ( > 0.05). CONCLUSION: Chemotherapy is accompanied by elevated fatigue scores and decreased life quality in NSCLC patients. Although mild moxibustion intervention could alleviate CRF in the patients and was not associated with any adverse events and liver and kidney toxicity when combined with chemotherapy, it could not improve their QoL.