Riparian buffer zones (RBZs) have been shown to be effective best management practices (BMPs) in controlling non-point source pollutants in waterbodies. However, the holistic sustainability assessment of individual RBZ designs is lacking. We present a methodology for evaluating the holistic sustainability of RBZ policy scenarios by integrating environmental and economic indicators simulated in three watersheds in the southeastern USA. We developed three unique sets of 40, 32, and 48 RBZ policy scenarios as decision management objectives (DMOs), respectively, in Back Creek, Sycamore Creek, and Greens Mill Run watersheds (Virginia and North Carolina) by combining the RBZ—widths with vegetation types (grass, urban, naturalized, wildlife, three-zone forest, and two-zone forest). We adapted the RBZ—hydrologic and water quality system assessment data of instream water quality parameters (dissolved oxygen, total phosphorus, total nitrogen, total suspended solids—sediment and biochemical oxygen demand) as environmental indicators, recently published by U.S. EPA. We calculated 20-year net present value costs as economic indicators using the RBZ’s establishment, maintenance, and opportunity costs data published by the Natural Resources Conservation Service. The mean normalized net present value costs varied by DMOs ranging from 4% (grass RBZ—1.9 m) to 500% (wildlife RBZ—91.4 m) across all watersheds, due primarily to the width and the opportunity costs. The mean normalized environmental indicators varied by watersheds, with the largest change in total nitrogen due to urban RBZs in Back Creek (60–95%), Sycamore Creek (37–91%), and Greens Mill (52–93%). The holistic sustainability assessments revealed the least to most sustainable DMOs for each watershed, from least sustainable wildlife RBZ (score of 0.54), three-zone forest RBZ (0.32), and three-zone forest RBZ (0.62), respectively, for Back Creek, Sycamore Creek, and Greens Mill, to most sustainable urban RBZ (1.00) for all watersheds.