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Past water distribution systems (WDS) management studies derived operation protocols to maximize WDS reliability by using residual chlorine as the sole surrogate parameter for water quality reliability. Albeit the advancement in mechanistic modeling to examine the WDS water quality, emerging water quality parameters of concern are not yet involved in solving WDS management problems. This paper attempts to overcome this limitation by developing a flexible decision-making framework -integrating EPANET-C, a mechanistic modeling tool for WDS water quality, with Analytic Hierarchy Process (AHP), a multi-criteria decision-making method - to rank the possible water quality parameter-based operating alternatives (organic matter and residual chlorine levels at the source points) for WDS. The uncertainty analysis was incorporated into the mechanistic modeling using the Monte Carlo method to realize insufficient knowledge about the complex biological and physicochemical interactions inside WDS. Six cases, each ranking the alternatives diversely, were applied to reflect the expert judgment impressions on the AHP outcomes. The consistency of the proposed decision-making framework was verified by deriving the operation protocol for two test networks by making trade-offs between the multiple and conflicting microbiological, chemical, and organoleptic quality criteria. The disinfection by-products formation control and taste and odor problems control emerged as the most critical water quality criteria determining the WDS performance under the operating alternatives examined. Altogether, the obtained results suggested the practicality of adopting a flexible operation protocol to maintain the water quality benchmarks over various plausible WDS performance scenarios, ranging from worst to best. [Display omitted] • General methodology to derive operation protocols for water distribution systems. • All-inclusive water distribution systems quality modeling considering uncertainty. • Flexible decision-making framework based on analytic hierarchy process. • Chemical and organoleptic quality criteria control the hierarchization process. • Flexible operation protocol minimizes contamination risks during operation. [ABSTRACT FROM AUTHOR]