Colon adenocarcinoma (COAD), a common digestive system malignancy, involves crucial alterations in mitochondria-related genes influencing tumor growth, metastasis, and immune evasion. Despite limited studies on prognostic models for these genes in COAD, we established a mitochondrial-related risk prognostic model, including nine genes based on available TCGA and MitoCarta 3.0 databases, and validated its predictive power. We investigated the tumor microenvironment (TME), immune cell infiltration, complex cell communication, tumor mutation burden, and drug sensitivity of COAD patients using R language, CellChat, and additional bioinformatic tools from single-cell and bulk-tissue sequencing data. The risk model revealed significant differences in immune cell infiltration between high-risk and low-risk groups, with the strongest correlation found between tissue stem cells and macrophages in COAD. The risk score exhibited a robust correlation with TME signature genes and immune checkpoint molecules. Integrating the risk score with the immune score, microsatellite status, or TMB through TIDE analysis enhanced the accuracy of predicting immunotherapy benefits. Predicted drug efficacy offered options for both high- and low-risk group patients. Our study established a novel mitochondrial-related nine-gene prognostic signature, providing insights for prognostic assessment and clinical decision-making in COAD patients.