A statistically optimized, catalyst-free method was developed for the direct nitration of salicylic acid to produce 5-nitrosalicylic acid, an important precursor to the anti-inflammatory drug mesalazine. The proposed approach provides a direct alternative to the conventional industrial route, which involves multiple reaction steps and the formation of undesired isomers. Response surface methodology (RSM) was employed to investigate the effects of temperature, nitric acid concentration, reaction time, and the salicylic acid (SA) to nitric acid molar ratio on the synthesis process. Quadratic models with high goodness of fit (R² > 0.99) were developed, and numerical optimization was subsequently performed to determine the model predicted optimum conditions. The RSM-predicted optimum was obtained at a temperature of −4.90 °C, a nitric acid concentration of 80.60%, a reaction time of 188.41 min, and an SA:HNO3 molar ratio of 1:10. Experimental validation under these conditions afforded a 5-nitrosalicylic acid yield of 48.9 ± 0.3% and a total isolated yield of 92.7 ± 0.4% (n = 3). The difference between the desired-product yield and the total isolated yield indicates moderate regioselectivity. The developed method enables the direct, catalyst-free nitration of salicylic acid, the simple isolation of highly pure 5-nitrosalicylic acid, and reduced generation of acidic aqueous waste, while providing a statistically optimized route to an important pharmaceutical precursor.