Objective To discuss the therapeutic efficacy and potential mechanisms of brucea javanica oil emulsion combined with 5-fluorouracil (5-FU) in patients with chemotherapy-resistant colon cancer. Methods From January 2021 to December 2024, 86 patients with chemotherapy resistance of colon adenocarcinoma diagnosed by pathology were selected as the research object, and randomly divided into control group (treated with 5-FU) and combined group (brucea javanica oil emulsion combined with 5-FU), with 43 cases in each group. The clinical efficacy, adverse reactions and changes of tumor proliferation index and glucose metabolism related index before and after treatment were compared between the two groups. Results The objective response rate (ORR) of patients in the combined group was significantly higher than that in the control group (P＜0.05), and there was no significant difference in disease control rate (DCR) between the two groups (P＞0.05). After six cycles of treatment, the expression levels of Ki-67, proliferating cell nuclear antigen (PCNA) and Cyclin D1, fasting plasma glucose (FPG), lactic acid (Lac), lactic acid dehydrogenase (LDH), glucose transporter 1 (GLUT1) in the combined group were significantly lower than those in the control group (all P＜0.05), AMP-activated protein kinase (AMPK) expression was significantly higher than that in the control group (P＜0.05), mammalian target of rapamycin (mTOR) expression was significantly lower than that in the control group (P＜0.05), and AMPK/mTOR ratio was significantly higher than that in the control group (P＜0.05). Conclusion Brucea javanica oil emulsion combined with 5-FU can improve the therapeutic response of chemotherapy-resistant colon cancer patients without increasing the obvious toxicity, which may be related to inhibiting the proliferation of tumor cells and regulating AMPK/mTOR-mediated metabolic reprogramming.