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Sweet sorghum is a C4 plant with great biomass potential yield in semi-arid environments. Under growing conditions affected by water shortage and nutrient deficiency, the optimal combination of irrigation and nitrogen (N) fertilization rate is a central issue for sustainable farming systems. In this paper, a N balance study was applied to sweet sorghum cv. Keller, managed under three irrigation levels (I0, I50, I100: 0, 50, and 100% crop evapotranspiration—ETc restoration) and four N-fertilization rates (N0, N60, N120, N180: 0, 60, 120, and 180 kg ha−1). The 15N-labelled fertilization technique was used to assess the fate of N fertilizer within the agroecosystem. Dry biomass yield was significantly affected by the irrigation, while N rates had no effect. Across N and irrigation levels, the isotopic composition showed that approximately 34% of N applied by fertilization was used by the crop, 56% remained in the soil at the end of the cropping season, 1.83% was leached as nitrate, and 1.72% was volatilized as ammonia. N-fertilizer uptake was the lowest in I0, while in N0, the soil was strongly N-impoverished since sorghum showed a great aptitude to benefit from the soil N reserve. An even N input/output system (i.e., N-output corresponded to N-input) was observed in the N120 treatment, and the soil N reserve remained unchanged, while the system was N-enriched (positive input/output) in N180. However, although beneficial for crop nutrition and soil N reserve for subsequent crops in rotation, the N180 treatment is unsustainable due to many environmental side effects in the agroecosystem.