<p>Colorectal cancer (CRC), presently one of the main contributors to cancer death globally, has increasing evidence pointing towards improper iron homeostasis as an underlying mechanism driving both its induction and progression. This review integrates the key elements of “crucial triad” pathogenesis in CRC, which include iron metabolism, chronic inflammation, and intestinal dysbiosis. This narrative review will draw on the literature regarding the mechanisms underlying the cytotoxicity of heme and on the mechanisms underlying the control of iron concentrations and ferroptosis initiated by heme exposure. The increased iron leads to expansion of the LP and enhances ROS production, contributing to DNA damage and tumor-promoting signaling pathways, such as NF-κB. Additionally, chronic inflammatory environments further disturb iron homeostasis systemically through hepcidin ferroportin regulation, creating a tumor microenvironment amenable to iron addiction in CRC. The conformation of a heme-rich diet may further damage the intestinal mucosa and shift intestinal microbiota to yield pro-inflammatory and genotoxins, such as N-nitrosocompounds and hydrogen sulfide, to further drive tumor-supportive inflammation. The target approaches for this iron-cancer link would involve iron-chelation therapy, hepcidin ferroportin pathway modulators, and ferroptosis-inducing agents, often contemplated concurrently with immune therapies. Translation into the clinical arena is limited by a lack of tumor selectivity, systemic iron depletion, and systemic iron deficiency anemia, together with a scarcity of strong iron-related biomarkers. Iron-targeted strategies are promising and need biomarker-driven, CRC-oriented clinical studies, as well as iron-dependence and ferroptosis-specialized management of on-target toxicities.</p>