Modern groundwater treatment processes often consist of pretreatment, membrane filtration, and disinfection steps. In order to achieve maximum water production and quality at the lowest possible production cost, treatment trains should be rationally designed based on contaminants present in the raw water and the target application. In this study, synthetic and natural groundwater (obtained from the Arbuckle-Timbered Hills Aquifer in SW Oklahoma) containing elevated concentrations of fluoride (F), arsenic (As), iron (Fe), and total dissolved solids (TDS) were treated using a range of water treatment trains, with the goal of producing drinking water. The impact of coagulant (Al 2 (SO 4 ) 3 •18H 2 O, aluminum sulfate) dosage, filtration media (quartz sand, manganese greensand, and activated alumina), and membranes (i.e., nanofiltration (NF) and brackish reverse osmosis) were investigated in terms of removal efficiency of target contaminants. Then, a water reuse model was employed to determine the optimal treatment train configuration and blending regime that maximizes quality while minimizing treatment cost. The water reuse model determined that the optimal treatment train consists of aluminum sulfate coagulation, activated alumina filtration, and NF and has a capability to produce potable water that meets drinking water guidelines at a production cost of $0.212/m 3 .