Objective: Ferroptosis and cuprotosis, two distinct mechanisms of programmed cell death, play key roles in colon cancer development. This study aimed to construct a prognostic model for predicting colon adenocarcinoma (COAD) prognosis based on the differential expression of cuproptosis-related ferroptosis genes (CFRGs). Methods: Transcriptomic data and clinical data of COAD patients were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. A combination of methods, including analysis of variance, Pearson correlation analysis, LASSO algorithm, and Cox regression was used to construct the CFRGs signatures. In addition, multiple algorithmic strategies were employed to explore the potential association between risk scores and immune infiltration features. Single-cell datasets were used to analyze model genes. Somatic mutations and drug sensitivities were compared across risk groups. Immunohistochemical analysis was performed to verify the expression of the main characterized genes. Results: We identified eight pivotal genes in constructing the CFRGs signature. Single-cell RNA sequencing revealed differential expression of CFRGs in the COAD tumor microenvironment. The nomogram confirmed that risk scoring serves as an independent prognostic factor for COAD. The high-risk group exhibited higher immune cell and stromal cell infiltration, as well as immune checkpoint expression. Patients in the high-risk group may benefit from olanzapine administration. Immunohistochemistry confirmed significantly higher expression of GLS and YAP1 in COAD tissues compared to adjacent non-cancerous tissues. Conclusions: The CFRGs risk prognosis model can effectively predict patients’ immune infiltration and immunotherapy response, providing a new reference basis for individualized treatment plans for COAD patients.