Objective <p>Frataxin (FXN) is a mitochondrial protein involved in various cellular processes. To date, the role of FXN in the initiation and progression of colon adenocarcinoma (COAD) remains unclear. This study aimed to investigate FXN expression in COAD and its involvement in COAD initiation and progression.</p> Methods <p>FXN expression in COAD was assessed via bioinformatics and immunohistochemistry (IHC) validation. The association between FXN expression and prognosis was evaluated using Kaplan‑Meier analysis and Cox regression analysis. Gene Ontology-Biological Process (GO-BP) enrichment analysis was performed to explore the potential biological functions of FXN in COAD. Functional assays (CCK-8, colony formation, Transwell) were used to confirm the critical role of FXN in COAD cell proliferation, migration, and invasion. R language, single‑sample gene-based enrichment analysis (ssGSEA), and correlation analysis were applied to identify associations between FXN expression and immune infiltration, immunotherapy response, and drug sensitivity.</p> Results <p>Compared with normal colon tissue, FXN expression was upregulated in COAD tissue (<i>p</i> &lt; 0.05), and high FXN expression predicted poor prognosis in COAD patients (<i>p</i> &lt; 0.05). GO-BP enrichment analysis revealed that FXN correlated with cell proliferation and microtubule dynamics (<i>p</i> &lt; 0.05). Downregulating FXN inhibited proliferation, migration, and invasion of COAD cells (<i>p</i> &lt; 0.05). FXN expression showed a correlation with several immune cells and immune cell markers, but no significant correlation with immunophenoscore (IPS). Drug sensitivity analysis indicated that FXN was associated with COAD samples’ sensitivity to several anticancer drugs (<i>p</i> &lt; 0.001).</p> Conclusions <p>FXN may promote the malignant phenotype of COAD and correlate with immune infiltration, serving as a prognostic biomarker and a potential reference for chemotherapy but not for immune checkpoint blockade.</p>