Water quality parameters from 2000 to 2020 were used to identify the spatial and temporal sulfate variations in estuaries of the northwestern Gulf of Mexico. Sulfate enrichment relative to conservative mixing was found to be associated with a low river discharge period from 2012 to 2014 in all estuaries. Based on reaction stoichiometry, sedimentary sulfide oxidation holds significant potential for reducing the alkalinity in estuarine waters. However, during this extreme drought, alkalinity enrichment was also occasionally observed in some of the southern estuaries along with sulfate enrichment, and when alkalinity depletion occurred, the magnitude of depletion was usually much less than what would be expected based on sulfide oxidation alone. This discrepancy can be partially explained by carbonate dissolution and other proton removal pathways (e.g., Fe-oxide dissolution), and by the uncertainties in the model used to estimate alkalinity enrichment/depletion. Under a changing climate, the close coupling between river discharge variation and estuarine sulfate dynamics will significantly impact estuarine carbonate chemistry.