Limited information is available concerning the influence of nitrogen fertilization jointly on yield response, nitrogen use efficiency (NUE) and grain quality of durum wheat under semi-arid Mediterranean conditions. The study focused on evaluating, through a systematic study, over three seasons in southern Italy the effects of three nitrogen fertilization rates (0, 80 and 160 kg N ha−1 – N0, N80 and N160), on grain yield, yield components, nitrogen efficiency indices and grain quality characteristics of three durum wheat genotypes (‘Creso’, ‘Trinakria’ and ‘Line 25’) from different breeding eras to achieve a more sustainable fertilization management of the durum wheat crop. We found that nitrogen fertilization at 80 kg N ha−1 was able to maximize the yield performances (2.1 t ha−1 year–1) of the crop and keep NUE index at an acceptable level (16.3 kg kg−1). On the other hand, nitrogen fertilization at 160 kg N ha−1 improved grain quality measured through protein (up to 14.3%) and dry gluten concentration (up to 12.8%), but had a detrimental effect on grain yield and nitrogen efficiency. Among the genotypes studied, ‘Trinakria’ showed the greatest potential to utilize nitrogen fertilization to improve grain yield and NUE (at N80) and quality (at N160), ‘Line 25’ made good use of N80 both for yield and quality, whereas ‘Creso’ proved wholly unresponsive to nitrogen. The effect of N fertilization on grain yield and N use efficiency depends on rainfall distribution, giving the best results when about 80% of total rainfall occurred from sowing to heading. Overall, our data show that in seasons with regular rainfall in quantity and distribution, combining no more than 80 kg ha−1 of nitrogen fertilization with genotypes characterized by a more efficient response to nitrogen, is a useful tool to improve the agronomic and quality performance of the crop, ensuring, at the same time, a more environment-friendly nitrogen fertilization.