Purpose: Colon cancer, one of the three deadliest cancers worldwide, has a high prevalence, especially in developing societies. Recently, our preclinical study demonstrated the strong anti-tumor effects of memantine on colon cancer in rats. This study aimed to investigate the effects of memantine (an NMDA receptor antagonist) in patients with metastatic colon cancer. Patients and Methods: In this randomized controlled clinical trial, 32 patients with metastatic colon cancer were randomized into two arms. The first arm received a chemotherapy regimen and the second arm received a chemotherapy regimen plus memantine 20 mg/day. The tumor size, metastasis, hematological parameters, CEA level, and N/L ratio were measured. Additionally, we assessed the safety and tolerability of this combination and its effect on the quality of life (QoL) of metastatic colon cancer patients. Results: Memantine reduced the colon tumor size in comparison to the control group patients (P=0.04). Also, in the memantine group, the metastasis was lower than in the control group (50% vs 87.5% respectively). Moreover, the memantine-treated group demonstrated reduced levels of CEA (P=0.01) as well as improved some hematological parameters. Also, quality of life was partially improved and no serious adverse effects were reported. Conclusions: Three-month adjuvant therapy with memantine reduces tumor size, metastasis, CEA level, and the N/L ratio, and also causes relative improvement of hematological parameters as well as the quality of life without causing any serious adverse effects. Therefore, memantine could be suggested as an appropriate adjuvant therapy in metastatic colorectal cancer.