Water is the key factor limiting crop production in irrigation water areas with high electric conductivities (ECs) in Northwestern China, where water scarcity and poor quality challenge food security and environmental sustainability. The accurate and efficient management of irrigation and fertilizer is important to obtain oriental melon (Cucumis melo L.) yield and to satisfy ecological water requirements in irrigation water areas with high-ECs. In this study, we evaluated the effects of irrigation amount (W), nutrient solution EC (E), and irrigation frequency (F) on melon growth and biomass, nutrient absorption ability, nutrient utilization efficiency, water use efficiency (WUE), fertilizer use efficiency (FUE), fruit quality, and yield. Specifically, we applied a quadratic orthogonal rotation combination design with three experimental factors at five levels (− 1.68, − 1, 0, 1, and 1.68) for a total of 23 treatments over two growing seasons during spring (2021S) and autumn (2020A). An entropy weight method was constructed, including 7 factors and 20 subfactors, to confirm representative indexes. After the values of representative indexes were normalized, the comprehensive evaluation system of oriental melon was established by the technique for order of preference by similarity to ideal solution method and the construction of structural equation models for the representative indexes of different factor pairs. W is the first factor for oriental melon’s integrated growth. Integrated growth, WUE, and FUE increased with W and exhibited a rise and subsequent fall with EC and F in 2020A, as well as with irrigation and nitrogen levels in 2021S. The nutrient utilization efficiency and fruit quality showed an “increase–decrease” trend with the increase in W and F and a decrease trend with the increase in E in 2020A and 2021S. In areas with high-EC irrigation water, a low-EC nutrient solution was found to be more suitable than a high-EC nutrient solution. When E was 3.53 mS/cm, F of seven times per day and the W values of 0.73 L/plant/day for autumn and 1.68 L/plant/day for spring were suitable for melon production. When E was 3.2 mS/cm, W of 1.2 L/plant/day and F of seven times per day were suitable for annual production. These irrigation schedules will greatly improve the WUE and yield of oriental melon, supporting the rational allocation of water resources of high-EC irrigation water regions in China.