Objective To study the effects of adding β⁃hydroxy⁃β⁃methylbutyrate (HMB) to oral nutritional supplements on elderly patients with stage Ⅰ-Ⅲ colon cancer to improve postoperative fatigue and quality of life. Method Colon cancer patients enrolled from January 2020 to June 2021 in Beijing Shijitan Hospital, First Affiliated Hospital of Kunming Medical University, Fourth Affiliated Hospital of Harbin Medical University, and Tenth People's Hospital Affiliated to Tongji University were hospitalized for radical resection. Divided into HMB intervention group and control group, by using the brief fatigue inventory (BFI) and the quality of life questionnaire⁃core 30 (QLQ⁃C30) scale to assess the degree of fatigue and quality of life of patients before and after surgery. Timed take⁃off test was used to assess the patient's overall physical fitness, white blood cell count and C⁃reactive protein to assess the changes in the patient's inflammation level. The patient's total hospital stay and total hospital expenses were recorded. Result The postoperative fatigue of the HMB intervention group was better than that of the control group in all dimensions (P<0.05). The overall quality of life of patients in the HMB intervention group was better than that in the control group [(41.2±2.6) vs (45.7±3.1), P=0.001]. Among them, in the field of quality of life symptoms, the scores of patients in the HMB intervention group were better than those in the control group[ (9.1±7.9) vs (15.2±8.2), P=0.008]. The postoperative white blood cell count of the HMB intervention group was lower than the control group [(5.5±1.6)×109/L vs (6.6±1.7)×109/L, P=0.042]. Conclusion Compared with regular oral nutritional supplements, oral nutritional supplements with HMB can improve the overall quality of life and fatigue better, and reduce the overall inflammation level of elderly patients with colon cancer after surgery.