Sustainability in agroecosystems relies on the optimized use of resources to achieve consistent yields while maintaining or improving soil health. The monitoring of soil quality is crucial when changes from rainfall-fed to irrigated crop systems occur. The objective of this study was to assess the impact of different crop successions in the Mediterranean area under irrigation and different technical practices. The soil nitrogen–phosphorous–potassium (NPK) and soil organic carbon (SOC) balances were observed in four fields with irrigated annual crops in a two-year succession timeframe, namely, sunflower–maize (P1), sunflower–clover (P2), maize–sunflower (P3), and alfalfa–alfalfa (P4). The SOC and nutrient balance, integrating the total irrigation, mineral fertilizers, and exported yield, was calculated for each farm. Except for maize–sunflower succession (P3), all fields presented a negative SOC balance at the end of the two-year crop succession, indicating losses from 2.84 to 4.91 Mg SOC ha−1 y−1. While in N-fixing plants the soil N decreased, in the remaining crops a surplus was observed, possibly leading to future N losses. The continuous depletion of soil P revealed a potential underestimation of this nutrient. Soil K appears to be related to specific crop management practices, namely, crop residue incorporation after harvest. In annual irrigated crops under Mediterranean conditions, crop succession can induce soil fertility degradation if conservation practices are absent.