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Abstract This study investigates dioxygen binding and 2‐oxoglutarate (2OG) coordination by two model non‐heme Fe^II/2OG enzymes: a class 7 histone demethylase (PHF8) that catalyzes the hydroxylation of its H3K9me2 histone substrate leading to demethylation reactivity and the ethylene‐forming enzyme (EFE), which catalyzes two competing reactions of ethylene generation and substratel‐Arg hydroxylation. Although both enzymes initially bind 2OG by using anoff‐line2OG coordination mode, in PHF8, the substrate oxidation requires a transition to anin‐linemode, whereas EFE is catalytically productive for ethylene production from 2OG in theoff‐linemode. We used classical molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM) MD and QM/MM metadynamics (QM/MM‐MetD) simulations to reveal that it is the dioxygen binding process and, ultimately, the protein environment that control the formation of thein‐lineFe^III‐OO⋅⁻intermediate in PHF8 and theoff‐lineFe^III‐OO⋅⁻intermediate in EFE.