Iron is an essential metal ion in the human body and usually dysregulated in cancers. However, a comprehensive overview of the iron‐related genes and their clinical relevance in cancer is lacking. In this study, we utilized the expression profiling, proteomics, and epigenetics from the Cancer Genome Atlas database to systematically characterized the alterations of iron‐related genes. There were multiple iron‐related genes with dysregulation across 14 cancers and some of these ectopic changes may be associated with aberrant DNA methylation. Meanwhile, a variety of genes were significantly associated with patient survival, especially in kidney renal clear cell carcinoma. Then differentially expressed genes were validated in clinical samples. Finally, we found deferoxamine and erastin could inhibit proliferation in various tumor cells and influence the expression of several iron‐related genes. Overall, our study provides a comprehensive analysis of iron metabolism across cancers and highlights the potential treatment of iron targeted therapies for cancers. We systematically analyzed dysregulation of iron metabolism genes using transcriptomics, epigenomics and proteomics data from the TCGA project. Our results showed that iron metabolism was dysregulated across different cancer types.