Release of lead (Pb) in drinking water from lead service lines has been extensively studied in single pipes, and the importance of water chemistry has been reported. However, the impact of variations in water chemistry parameters during water supply from the treatment plant to the downstream distribution network is crucial to understand toward minimizing lead release rates and has not yet been researched. This study proposes a comprehensive framework for investigating the changes in dissolved lead concentrations resulting from variations in the concentration of water chemistry parameters (such as pH, orthophosphate, free chlorine disinfectant residual, dissolved inorganic carbon and natural organic matter). The framework accounts for changes in the chemistry as water flows in a typical, full-scale water distribution network from the treatment plant to the homes through iron distribution mains and lead service lines under dynamic hydraulic conditions. The approach comprises the development of a multispecies reactive transport model for simulating important water chemistry reactions in distribution mains using EPANET-MSX. This water chemistry model is coupled in the framework with a mass transfer-based model for lead release from service lines. The resulting trends of water chemistry parameters variations with water age are qualitatively verified with general trends from experimental and field studies. The influence of complex water chemistry on the spatial and temporal profile of lead levels are analyzed by generating holistic simulations for a full-scale water distribution network case study. Three relevant treatment scenarios of pH adjustment, disinfectant dosage, and orthophosphate addition are presented to reflect the importance of the causal relationship between water chemistry variations in distribution mains and dissolved lead release from service lines. A strong correlation is observed between % change in dissolved lead levels and variations in pH, free chlorine residual, and orthophosphate residual in distribution mains. Further, practical implications for the use of the proposed framework to identify lead release hotspots, suggest potential sampling locations, and optimize remedial treatment measures to control lead dissolution for safe water supply are discussed. © 2020 American Society of Civil Engineers.