Abstract Background Wheat productivity in irrigated arid and semi-arid regions is constrained by low soil fertility and inefficient use of mineral fertilizers. A process-level understanding of how integrated organic and mineral fertilization interacts with genotype to control yield formation, grain nitrogen (N) partitioning, and nitrogen use efficiency (NUE) in coarse-textured soils remains limited. Here, we quantified the combined effects of NPK fertilization regime (100% soil application vs. increasing proportions of fertigation), compost rates, and wheat (Triticum aestivum L.) genotype on yield, yield components, grain quality, and NUE in a low-fertility sandy soil over two growing seasons in an arid environment. We hypothesized that increasing fertigation would additively enhance yield components and NUE with compost, with diminishing returns at high compost rates, and that genotypes would differ in the relationship between grain yield and grain protein concentration. Methods A split-split plot design included three cultivars (Sakha-95, Sids-14, Misr-1), four NPK regimes (F1: 100% soil; F2–F4: 50–100% fertigation), and three compost rates (12, 24, and 36 t ha⁻¹). Results Full fertigation (F4) increased grain yield and NUE by 49.8% relative to 100% soil application, primarily by increasing spike density, grains spike⁻¹ and 1000-grain weight. Compost further enhanced yield and NUE, with 36 t ha⁻¹ giving 18% higher grain yield than 12 t ha⁻¹. Genotypes differed markedly: Sakha-95 achieved the highest grain and biological yields and NUE, whereas Sids-14 and Misr-1 produced higher grain protein. Path analysis showed that spikes m⁻², 1000-grain weight, and fertile spikelets spike⁻¹ had the largest direct effects on grain yield, while principal component analysis revealed that combinations of high fertigation and high compost clustered with superior trait profiles. Intensive fertigation led to diminishing returns from compost at high rates, indicating an optimum organic input under high soluble nutrient supply.