Brains are among the first organs to decompose after death, yet also some of the most commonly preserved soft tissues in the archaeological and fossil records. This paradox between rapid early decay and long-term survival has been known for at least four centuries, but has yet to be explained. Here we decayed mouse carcasses for six months in four burial environments differing in water and oxygen availability, and tracked changes in brain proteins using high-resolution mass spectrometry. Oxygen availability exerted the main control on molecular fate: oxygen-rich conditions produced extensive protein loss, whereas oxygen-poor, especially waterlogged, conditions favoured retention of a distinctive subset of decay-resistant peptides. These surviving sequences were more structurally ordered, enriched in chemically reactive amino acids and in regions that bind metals and lipids, and bore modification patterns consistent with crosslinking rather than fragmentation. Together, these features support a molecular model in which, in waterlogged, oxygen-poor graves, the brain’s own molecular composition and structure direct post-mortem chemistry towards the formation of stable, crosslinked products. By linking local protein structure and chemistry to environmental context, our results move brain preservation from anomaly to expectation: solving the long-standing puzzle of why brains outlast other soft tissues, providing a basis for predicting when brain and other soft tissues are likely to survive, and suggesting shared features with molecular processes underpinning neurodegeneration and brain ageing.