Cuproptosis is the latest cell death type caused by enhanced mitochondrial-dependent energy metabolism. This study plans to establish a survival prognosis model for colon adenocarcinoma (COAD) patients based on cuproptosis-related genes (CRGs). We investigated the genetic alterations of CRGs in COAD based on The Cancer Genome Atlas database and validated in the GSE41328 dataset. Our results showed that LIPT1, PDHA1, GLS, and CDKN2A had significantly higher expression in COAD tissues than in normal tissues, while FDX1, DLD, and MTF1 had significantly lower expression in COAD tissues than in normal tissues (|(log2(fold change))| > 2, p < 0.05). DLD (hazard ratio (HR): 0.658; 95% confidence interval (CI): 0.445, 0.974; p = 0.037) and CDKN2A (HR: 1.785; 95% CI: 1.200, 2.654; p = 0.004) expressions were linked with overall survival throughout a log-rank test. CRG prognostic scores exhibited an area under the curve of 0.737, 0.646, and 0.633 at 1, 3, and 5 years. Patients with a high-risk factor suffered from poor prognosis (HR = 1.514; 95% CI: 1.022, 2.243; p = 0.0386). An independent validation dataset (GSE41328 (N = 20)) confirmed the above results. The CRGs’ signature may be used as a prognostic predictor for COAD patients, providing unique insights into anticancer therapy.