This paper describes a novel cellular automata-based mesoscale multispecies reactive-transport (CA-MSRT) model for predicting microbial regrowth and trihalomethanes (THMs) formation in water distribution systems (WDSs) under different loading and temperature conditions. The kinetic models to analyze the degradation of chlorine, natural organic matter (NOM), and microbial biomass and formation of THMs during secondary chlorination applications are also proposed. The CA-MSRT model was applied to a benchmark WDS with two water sources (river and lake), a problem well tested by many researchers. A 60% reduction in total organic carbon (TOC) combined with chlorine application of 1 mg/L at the lake water source has resulted in regulating the microbiological and chemical quality of the delivered water at the outlet points. Results indicate that supplementing the chlorine levels through secondary disinfection stimulates formation of THMs and thereby compromises the chemical quality of the delivered water. It was found that the fractions of THMs formed from the carbon content associated with attached and suspended microbial biomass were only <2%, and the remaining fractions were derived from NOM. Overall, the study confirmed the benefits of reducing the organic matter content and optimal selection of the chlorine dose at the source point in contriving the water quality at the outlet points of WDSs. © 2020 American Society of Civil Engineers.