Abstract: Per- and polyfluoroalkyl substances (PFAS) are of significant environmental concern due to their exceptional chemical stability and bioaccumulation potential, posing serious threats to ecosystems and human health. The extraordinary strength of C–F bonds renders PFAS recalcitrant to conventional water treatment technologies, which typically fail to achieve complete degradation or mineralization. Therefore, developing efficient and targeted removal techniques has become a major challenge in environmental science. Iron-based materials, owing to their natural abundance, environmental compatibility, and strong redox activity associated with multiple valence states, have shown great promise for PFAS degradation. This review systematically summarizes recent advances in PFAS degradation using iron-based systems, with a focus on material properties and reaction mechanisms. Iron-based systems are categorized into homogeneous iron species (Fe²⁺/Fe³⁺ ions) and heterogeneous materials, including zero-valent iron (ZVI), iron-bearing minerals, multimetallic iron composites, and supported iron materials. Their physicochemical properties, affinity for PFAS, and catalytic reactivity are comprehensively evaluated. Structural design and active-site engineering are critical for enhancing catalytic performance. Compared with conventional ZVI, which suffers from limited reactivity, novel iron-based nanocomposites—such as those modified with graphene or encapsulated in nitrogen-doped graphene-like structures—can achieve defluorination efficiencies of 50%–100%. Regarding degradation mechanisms, iron-based materials facilitate PFAS transformation via multiple pathways: (i) reductive processes, including direct electron transfer from ZVI, as well as reactions with hydrated electrons or atomic hydrogen radicals; (ii) oxidative processes driven by hydroxyl and sulfate radicals that target head groups and C–F bonds, along with the ligand-to-metal charge transfer (LMCT) mechanism enabling photoinduced electron transfer; (iii) redox synergy, in which reductive defluorination or chain-shortening lowers the reaction barrier and promotes subsequent radical oxidation; and (iv) iron-based material–microbial synergy, where iron-based materials mediate extracellular electron transfer and act in concert with microbial surface reductive activity. Among these pathways, reductive degradation is currently the most effective approach for deep defluorination of long-chain PFAS, while the LMCT mechanism offers unique advantages in photocatalytic oxidation by lowering energy barriers. Despite the remarkable potential of iron-based materials, their practical application faces several challenges. Short-chain PFAS, due to their weak hydrophobicity and low adsorption affinity, exhibit significantly lower degradation efficiencies than their long-chain counterparts and tend to accumulate as recalcitrant intermediates, complicating complete mineralization. Additional challenges include iron leaching, surface passivation, and interference from complex water matrices. Future research should focus on developing iron-based composites with enhanced stability and reactivity, advancing pilot-scale and field applications to evaluate economic and technical feasibility, and exploring the coupling of iron-based materials with renewable energy sources for sustainable operation. This review aims to provide a theoretical foundation for the rational design of iron-based materials and their application in PFAS pollution control.