We demonstrate a remarkable change of chemical trend of iron under high pressure that is of great importance for understanding the distribution of elements in the Earth’s mantle and core. Using a massive-scale first principles study, we show that while reacting with p-block elements under increasing pressure from ambient to that of Erath’s core, iron tends to reverse its chemical nature, changing from an electron donor (reductant) to an electron acceptor, and oxidizes p-block elements. Such reverse chemistry significantly impacts the stoichiometries, bond types and strengths, structures and properties of iron compounds under deep planetary conditions, making many p-block elements that are conventionally labeled lithophile or chalcophile to highly siderophile. The chemical binding strengths with iron show an inverse correlation with the depletion of p-block elements in silicate Earth. Furthermore, silicon shows a distinct anomaly in its bonding to iron, which suggests silicon may readily be incorporated into Earth’s core.