Understanding the variation of chlorine concentrations in water distribution systems is important for determining the schedule of rechlorination. Maintaining an appropriate chlorine concentration in domestic tap water and a sustainable residual chlorine in water distribution systems is an important commitment to ensure high drinking water quality. A generic modeling framework is proposed to amalgamate most widely used existing chlorine decay models. This framework gives rise to 14 distinct model structures. A pilot-scale water distribution system was designed and fabricated to investigate the performance of the proposed modeling framework. A hybrid calibration algorithm, obtained using a combination of the genetic algorithm and the particle swarm optimization, was introduced to rigorously calibrate the parameters of the various models. The adequacy of the performance of the various models was evaluated using both the Akaike information criterion and the Bayesian information criterion. A reliable relationship between the Reynolds numbers and the model parameters was obtained for the relatively simple model structure. The parameter spaces of several chlorine decay models can be configured, and equations of parameters for corresponding flow condition can be delineated. The generic model robustly predicted the chlorine concentration when the Reynolds numbers were between 15,000 and 40,000.