To explore the effect of Jiawei Huoluoxiaolingdan on the pain and serum substance P (SP), β-endorphin (β-EP) and prostaglandin E2 (PGE2) levels in patients with advanced cancer pain. Methods? A total of 60 patients with advanced cancer pain who were admitted to Yangjiang Hospital of Traditional Chinese Medicine from March 2019 to February 2021 were divided into the control group (30 cases, given Oxycodone hydrochloride sustained-release tablets, and combined with Instant-release Morphine depending on the situation) and the observation group (30 cases, combined with Jiawei Huoluoxiaolingdan on the basis of the control group) according to the random number table, both groups were given 2 weeks of treatment. The clinical effects of patients in the two groups after treatment were compared, the serum pain mediator levels, the score of brief pain assessment scale (BPI) and the level of quality of life before and after treatment of patients in the two groups were compared. Results? After treatment, the total clinical pain relief rate of patients in the observation group was 86.67%, which was higher than that 63.33% of patients in the control group; compared with before treatment, the serum SP, PGE2 levels and BPI scores (the most severe degree of pain, the least pain degree, the average pain degree, the current pain degree) of patients in the two groups after treatment reduced, and the observation group was lower than the control group, while the serum β-EP level and quality of life score (family understanding and cooperation, colleague’s understanding and cooperation, mental state, sleep status, daily life, facial expression, fatigue level, pain level, own understanding of cancer, dietary status, treatment attitudes) increased, and the observation group was higher than the control group (all P <0.05). Conclusion? Jiawei Huoluoxiaolingdan can effectively relieve the clinical symptoms of patients with advanced cancer pain, inhibit the secretion of pain mediators, reduce the pain of patients, improve the quality of life, and improve clinical efficacy.