Exploring the response of soil nutrients to agricultural land use and its landscape pattern is of great significance for the rational use of agricultural land, precise agricultural policies, and ecological environment protection in major grain-producing areas. By constructing a research framework on the response of soil nutrients to agricultural land use and its landscape pattern, using methods such as landscape pattern zoning and geographic detectors, and taking Tongshan District, Xuzhou City, Huaihai Economic Zone as an example, this study reveals the diversity and uniqueness of the differences in soil nutrients' response to agricultural land use and its landscape pattern within the major grain-producing areas and analyzes their influencing factors. The results show that: (1) the average soil nutrient content in paddy and arid fields is higher than that in orchard land and irrigated land, but the soil organic matter content is generally low, the total nitrogen content is moderate, and the available phosphorus and potassium content are relatively sufficient; (2) The average organic matter content in areas with large and clustered patches and small and fragmented patches is higher, while the average content of available phosphorus, available potassium, and total nitrogen in areas with large and complex patches is higher than that in areas with smaller patches; (3) The spatial differentiation of organic matter and total nitrogen is greatly influenced by natural factors, available phosphorus is greatly influenced by human factors, and available potassium is jointly affected by natural and human factors; (4) Compared with hilly areas with higher elevations, plain areas have more diversified and intensive agricultural land use, with more contiguous landscape patches and relatively high soil nutrient content, which promotes higher grain yield per unit area and higher socio-economic level; (5) The research framework constructed in this article is more suitable for exploring the impact of agricultural land use and landscape patterns on soil nutrients in major grain-producing areas, represented by Tongshan District. The research results can provide reference and guidance for the rational use of agricultural land, precise nutrient application, and soil quality and fertility evaluation in Huaihai Economic Zone and other areas similar to Tongshan District.