There has been limited study on the performance of miscanthus (Miscanthus × giganteus) on Coastal Plain soils in the Mid-South United States and use of poultry litter (PL) with miscanthus. This study examined the response of miscanthus growing on a low-fertility soil to N and PL, including effects of PL on water quality. A randomized complete block experiment on Ruston soil (fine-loamy, siliceous, semiactive, thermic Typic Paleudults) compared five fertilizer treatments: 0, 80, and 160 kg N ha−1 y−1 as urea or PL, applied 2010 through 2013, and native vegetation (NV). Data included yields, tissue nutrients, and runoff from subplots of NV, 0, and PL, 2010 to 2014; fertility parameters in surface (0–15 cm) soil, 2009 to 2015; organic C (OC) and oxalate-extractable Al, Fe, and P with depth, 2010; and fertility parameters (including OC, total N, and total and inorganic P) with depth, 2015. Yields exhibited a 3-year lag before a maximum of 18 Mg ha−1 in 2014 and were not increased by N fertilization. Nutrient removal was low, leading to increased P with PL in 0- to 15-cm soil but no evidence of P leaching below 30 cm. Runoff P was increased by PL at the higher rate (0.40 kg P ha−1 y−1 greater than no PL). Although use of PL alone to replenish nutrients would lead to high P loss, supplementing a reduced PL rate with non-P fertilizer might be sustainable. Miscanthus did not increase soil OC or affect water quality compared with NV.