Geological evidence of Earth’s Great Oxidation Event (GOE) and Neoproterozoic Oxygenation Event (NOE) provides a timeline of atmospheric oxygen rise, but a critical gap remains in understanding how organisms genetically adapt to shifting redox conditions. This study bridges this gap by analyzing carbon oxidation state (Zc)—a quantitative measure determined by amino acid composition—across 178 genomes spanning diverse metabolic groups and reconstructed ancestral sequences of key enzymes. Our analyses reveal consistent oxidation patterns correlating with major oxygenation events: Class II methanogens show genome-wide elevated Zc compared to Class I methanogens, with adaptations persisting across proteins with varying expression levels and different GC contents and metabolic costs. Eukaryotic gene age groups exhibit increasing Zc for proteins dating to the GOE period, with unicellular eukaryotes showing a secondary peak during the NOE while multicellular lineages display decreasing Zc—suggesting physiological constraints in oxygen delivery to tissues in complex organisms. Remarkably, reconstructed ancestral Rubisco sequences demonstrate increasing oxidation state along evolutionary branches, particularly around the GOE. Thermodynamic analysis reveals that photosynthetic organisms, represented by Rubisco, occupied more oxidizing environments compared to methanogens and non-photosynthetic ammonium oxidizers, suggesting spatial redox gradients during the GOE period. These findings establish Zc as a dependable genomic proxy for reconstructing ancient redox conditions and organismal adaptations, providing a biological record that complements geological evidence. By analyzing protein composition across phylogenetically diverse organisms, we offer a novel approach to quantifying the coevolutionary dynamics between life and Earth’s oxygenation history, aligning with fundamental concepts in energy minimization and adaptive evolution.