Mineral stabilization of soil organic matter is an important regulator of the global carbon (C) cycle. However, the vulnerability of mineral-stabilized organic matter (OM) to climate change is currently unknown. We examined soil profiles from 34 sites across the conterminous USA to investigate how the abundance and persistence of mineral-associated organic C varied with climate at the continental scale. Using a novel combination of radiocarbon and molecular composition measurements, we show that the relationship between the abundance and persistence of mineral-associated organic matter (MAOM) appears to be driven by moisture availability. In wetter climates where precipitation exceeds evapotranspiration, excess moisture leads to deeper and more prolonged periods of wetness, creating conditions which favor greater root abundance and also allow for greater diffusion and interaction of inputs with MAOM. In these humid soils, mineral-associated soil organic C concentration and persistence are strongly linked, whereas this relationship is absent in drier climates. In arid soils, root abundance is lower, and interaction of inputs with mineral surfaces is limited by shallower and briefer periods of moisture, resulting in a disconnect between concentration and persistence. Data suggest a tipping point in the cycling of mineral-associated C at a climate threshold where precipitation equals evaporation. As climate patterns shift, our findings emphasize that divergence in the mechanisms of OM persistence associated with historical climate legacies need to be considered in process-based models.