Soil degradation in arid regions poses a critical environmental challenge to agricultural sustainability, yet the drivers of this degradation and their impacts on nutrient availability remain insufficiently understood. A significant knowledge gap exists in quantitatively linking long-term soil degradation processes to the decline in availability of key macronutrients in arid agroecosystems. This study integrates historical datasets (1975–2024), field observations, GIS mapping, and advanced statistical modeling to identify key chemical and physical soil degradation drivers and quantify their impacts on soil available nitrogen, phosphorus, and potassium in the eastern Nile Delta of Egypt, a key arid agricultural region facing severe land degradation. Results identified escalating soil salinity (EC +123%) and sodicity (sodic area: 276–1084 km2) as primary degradation drivers over five decades, alongside severe soil organic matter depletion (−33.9%) and reduced the stratification ratio of soil organic carbon (SR of SOC, calculated as the ratio of SOC concentration in surface to subsurface soil; −52.2%). The structural equation modeling and random forest analysis confirmed that reduced SOC SR and increased waterlogging lead to soil degradation via increasing salinity, exchangeable sodium percentage, and compaction (higher bulk density). As a result, a reduction in available nitrogen (−12.2%), phosphorus (−36.4%), and potassium (−11.2%) was recorded. Specifically, increased soil pH and bulk density reduced available phosphorus, while reduced SOC SR drove the reduction of available nitrogen and potassium. Consequently, the extent of areas classified as experiencing very high soil degradation more than doubled, expanding from 731 to 1760 km2. This study provides quantified evidence linking specific degradation drivers to nutrient declines in the Nile Delta, highlighting an urgent need for sustainable management (e.g., improved irrigation, organic amendments, and salinity control) to ensure agricultural sustainability.