Abstract: To determine the optimal fertilization program for Rheum tanguticum, we evaluated the effects of different amounts of nitrogen, phosphorus, and potassium fertilizers on the yield and economic benefits of the plant, based on the ‘3414’ fertilization design. Based on plant yields and economic benefits, the success of the fertilization treatments was ranked as follows: fertilized>non-fertilized, and NPK>P>N>K. The effects of pairwise interactions on yield and economic benefits, from strongest to weakest, were ranked as follows: NP> PK>NK and PK>NP>NK, respectively. In all treatments except for the excess N treatment, total anthraquinone, total ash, and water content in the R. tanguticum roots met the standard of the Pharmacopoeia of the People’s Republic of China. The data for plant yield and economic benefits under the different fertilizer treatments fitted well with ternary quadratic, binary quadratic, and simple quadratic equations. Therefore, these equations represented the relationships between fertilizer quantity and yield/economic benefits. Taken together, the results of this study show that the fertilization program producing the highest yield (12384.3 kg/ha) under the local experimental conditions was N 74.06 kg/ha, P 55.07 kg/ha, and K 36.56 kg/ha. The fertilization program resulting in the best economic benefits was N 73.33 kg/ha, P 54.58 kg/ha, and K 36.37 kg/ha, resulting in 12012.6 kg/ha of yield and 196126.0 yuan/ha of economic benefit.