Abstract： Objective： To observe the efficacy of Huangqi Jianzhong Decoction combined with thunder-fire moxibustion in the treatment of colorectal cancer with cancer-related fatigue （CRF） of qi deficiency type， and to explore its effects on serum neurotransmitter levels. Methods：A total of 100 patients with colorectal cancer with CRF of qi deficiency type treated at Luoyang Branch of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine from October 2022 to October 2025 were enrolled. They were randomly divided into the study group and the control group using the random number table method，with 50 cases in each group. The control group received Huangqi Jianzhong Decoction， while the study group received thunder-fire moxibustion in addition to Huangqi Jianzhong Decoction. Both groups were treated for four weeks. The clinical efficacy， changes in traditional Chinese medicine syndrome scores，Revised Piper Fatigue Scale （RPFS） scores，Karnofsky Performance Status （KPS） scores，and serum levels of neurotransmitters [5-hydroxytryptamine （5-HT）， norepinephrine （NE）， dopamine （DA） ] were compared between the two groups. Results： After treatment， the total effective rate was 86.00% （43/50） in the study group and 64.00% （32/50） in the control group， with a statistically significant difference between the two groups （P＜0.05） . After treatment， traditional Chinese medicine syndrome scores in both groups decreased compared with those before treatment （P＜0.05），and the traditional Chinese medicine syndrome score in the study group was lower than that in the control group （P＜0.05） . After treatment， RPFS scores in both groups decreased compared with those before treatment （P＜0.05），and the RPFS score in the study group was lower than that in the control group （P＜0.05） . After treatment， serum levels of 5-HT and DA in both groups increased compared with those before treatment （P＜0.05），while NE levels decreased （P＜0.05）；the study group showed higher levels of 5- HT and DA （P＜0.05） and a lower level of NE （P＜0.05） than the control group. After treatment，KPS scores in both groups increased compared with those before treatment （P＜0.05）， and the KPS score in the study group was higher than that in the control group （P＜0.05）. Conclusion：Huangqi Jianzhong Decoction combined with thunderfire moxibustion can improve the clinical efficacy in the treatment of colorectal cancer with CRF of qi deficiency type. The combined treatment regimen has certain advantages over Huangqi Jianzhong Decoction alone in alleviating the condition and regulating neurotransmitter levels.