The oxygen reduction reaction (ORR) is a crucial chemical process, which contributes significantly to the energy efficiency of fuel cells and metal-air batteries. Although Pt and its alloys are known as the most efficient catalysts for ORR, its high costs and scarcity limits their applications. Alternatively, Fe–N–C single-atom catalysts (SACs) have attracted the most interest owing to their low-cost and facile preparation methods. Metal macrocycles, such as iron phthalocyanines (FePc), are the precursors most widely used to prepare the ORR catalysts in fuel cells and metal-air batteries. However, limited progress has been made in improving their electrocatalytic activity and durability. Indeed, FePc has demonstrated to suffer from severe degradation in the acidic fuel cell environments, commonly attributed to demetallation and/or degradation by ORR intermediates. In this seminar, recent advances in the theoretical characterization of SAC for ORR will be highlighted, using DFT-based ab-initio calculations, including molecular dynamic simulations. The focus will be the interaction of FePc with oxygen molecules and mechanisms of FePc deactivation under operational conditions, including explicitly aqueous environments that reproduce acid and alkaline media.