Water content plays a critical yet ambivalent role in the physical and geochemical stability of mine tailings and waste rock, but its effects on individual chemical weathering reactions (dissolution and precipitation) and bulk water quality remain poorly understood. We experimented with synthetic waste rock to quantitatively reconcile modal and textural mineralogical parameters (mineral size, association, and liberation) with leachate quality at different water saturation levels (5–100%). Leachate pH consistently decreased from a 13-week average of 6.14 at 100% saturation to 5.37 at 5% saturation. Simultaneously, mineralogical analyses revealed a reduction in the size of carbonate phases over the course of weathering, decreasing from 200 µm to 145 µm as water saturation increased from 5% to 100%, which could be a contributing factor to more alkaline pH in samples with higher water saturation. Total concentrations of iron (Fe) and copper (Cu) in solution increased with lower moisture, with Cu concentrations increasing 24-fold in samples at 5% saturation compared to full saturation. In contrast, arsenic (As) concentration increased with higher moisture levels, which we attribute to reduced galvanic protection of As-bearing pyrite from oxidation. Multivariate statistical evaluation allowed us to uncover correlations between water chemistry and mineralogical data (i.e., sulfide associations or phase perimeters) and to explain chemical differences between samples, particularly those at 100% and 5% water saturation. Our findings underscore the importance of conducting quantitative mineralogical investigations on mine waste materials and considering their stored water content in the formulation of mine waste management strategies.