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Lake Mead located in the Arizona–Nevada region of the Mohave Dessert is a unique and complex water system whose flow follows that of a warm monomictic lake. Although monomictic lakes experience thermal stratification for almost the entire year with a period of complete mixing, the lake on occasion deviates from this phenomenon, undergoing incomplete turnovers categorized with light stratifications every other year. The prolonged drought and growing anthropogenic activities have the potential to considerably impact the quality of the lake. Lake Mead and by extension the Boulder Basin receive cooler flow from the Colorado River and flow with varying temperatures from the Las Vegas Wash (LVW), which impacts its stratification and complete turnovers. This study analyzes four key water quality parameters (WQPs), namely, total dissolved solids (TDS), total suspended solids (TSS), temperature, and dissolved oxygen (DO), using statistical and spatial analyses to understand their variations in light of the lake stratifications and turnovers to further maintain its overall quality and sustainability. The study also evaluates the impacts of hydrological variables including in and out flows, storage, evaporation, and water surface elevation on the WQPs. The results produced from the analysis show significant levels of TDS, TSS, and temperature from the LVW and Las Vegas Bay regions compared with the Boulder Basin. LVW is the main channel for conveying effluents from several wastewater treatment facilities into the lake. We observed an increase in the levels of TDS, TSS, and temperature water quality in the epilimnion compared with the other layers of the lake. The metalimnion and the hypolimnion layer, however, showed reduced DO due to depletion by algal blooms. We observed statistically significant differences in the WQPs throughout various months, but not in the case for season and year, an indication of relatively consistent variability throughout each season and year. We also observed a no clear trend of influence of outflows and inflows on TDS, temperature, and DO. TSS concentrations in the lake, however, remained constant, irrespective of the inflows and outflows, possibly due to the settling of the sediments and the reservoir capacity. [ABSTRACT FROM AUTHOR]