Subsoils store at least 50% of soil organic carbon (SOC) globally, but climate change may accelerate subsoil SOC (SOC sub ) decomposition and amplify SOC-climate feedbacks. The climate sensitivity of SOC sub decomposition varies across systems, but we lack the mechanistic links needed to predict system-specific SOC sub vulnerability as a function of measurable properties at larger scales. Here, we show that soil chemical properties exert significant control over SOC sub decomposition under elevated temperature and moisture in subsoils collected across terrestrial National Ecological Observatory Network sites. Compared to a suite of soil and site-level variables, a divalent base cation-to-reactive metal gradient, linked to dominant mechanisms of SOC sub mineral protection, was the best predictor of the climate sensitivity of SOC decomposition. The response was "U"-shaped, showing higher sensitivity to temperature and moisture when either extractable base cations or reactive metals were highest. However, SOC sub in base cation-dominated subsoils was more sensitive to moisture than temperature, with the opposite relationship demonstrated in reactive metal-dominated subsoils. These observations highlight the importance of system-specific mechanisms of mineral stabilization in the prediction of SOC sub vulnerability to climate drivers. Our observations also form the basis for a spatially explicit, scalable, and mechanistically grounded tool for improved prediction of SOC sub response to climate change.