Abstract: The study aims to promote the development of watermelon industry in Ningxia and solve the problems of water resources and fertilizer waste caused by unreasonable irrigation and fertilization, in order to control the incidence of watermelon disease, and improve the yield and quality of watermelon. An experiment of four factors and five levels of quadratic regression orthogonal rotational combination design was carried out, and a mathematical model was constructed with the yield as the objective function, and pruning, density, the application amount of phosphorus and application amount of nitrogen as 4 factors of dependent variables. The research results showed that the main factors’ effect on yield had an order as: density, nitrogenous fertilizer, pruning, phosphate fertilizer; while factor interaction effect on yield had an order as: pruning×density, P×N, pruning×P. In conclusion: with 2-3 vine pruning, pure nitrogen fertilizer of 150 to 180 kg/hm², P fertilization (P₂O₅) of 150 to 180 kg/hm² and density of 80000 plants/hm², the output could reach more than 60000 kg/hm² and the agronomic measures combination scheme could be regarded as the optimal. The scheme can reduce the utilization of water resources and fertilizer, and provide the theoretical basis for the cultivation of watermelon industry in Ningxia.