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Cotton has been the main agronomic crop in northeast Louisiana for many years. However, this mono-crop system has led to the decline of many soil properties. The application of organic amendments, such as poultry litter, has the potential to alleviate these problems, especially when paired with other best management practices. However, little information is available on these highly degraded soils. Therefore, a field trial was conducted to evaluate the effect of poultry litter applications paired with other best management practices, such as tillage and cover crops, on cotton production. Trials were conducted from 2008 through 2011 in Winnsboro, Louisiana. Poultry litter was applied at the rate of 0, 3.3, and 6.7 Mg ha-1. Litter applications were evaluated over both conservation and conventional tillage operations as well as with and without a winter cover crop. Additionally, to simulate traditional production practices, a treatment which fertilizer was applied through an inorganic source was included. Early season first flush run-off was collected following rainfall events twice; early in the growing season and prior to reproductive stages. Following harvest, soil samples were collected and total soil analysis was conducted. Cotton lint yields of the poultry litter treatments yielded significantly (P<0.05) higher than those that received inorganic fertilizers. A significant build-up of Mehlich-3 extractable soil test P levels was found when poultry litter was incorporated compared to surface applied. However, surface poultry litter application resulted in a significant increase in first flush run-off P levels compared to incorporated litter. Poultry litter can be used as a soil amendment in northeast Louisiana, especially on the highly degraded soils to improve their productivity as well as sustainability; however, proper management needs to be emphasized to minimize environmental impact.