Tow field experiments were carried out at the Experimental Farm of the Water Studies and Research Complex (WSRC) Station, National Water Research Center, in Abu Simbel, Toshka Region, Egypt during two winter seasons 2015-16 and 2016-17. The main objectives were to study the effect of different irrigation levels [A 1 =100% of crop water requirements (ET crop), A 2 =80% ET C and A 3 =60% ET C ], three rates of nano-fertilizer (lithovit) (B 1 =0, B 2 = 200 and B 3 =400ppm), three levels of nitrogen fertilizer (C 1 =60, C 2 =80 and C 3 =100 kg N fed-1) and their interactions on yield and its component, water use efficiency (WUE), fertilizer use efficiency (FUE) and quality of durum wheat plants. The experimental design was a strip-split plot with three replications. The tested agronomic traits were: plant height, No. of tillers m-2 , spike length, No. of grains spike-1 , 1000-grain weight, grain yield, water use efficiency (WUE), irrigation use efficiency (IWUE), fertilizer use efficiency (FUE) as well as protein and ash content, hectoliter weight and Hegberg falling number. The results indicated that the irrigation levels, nano-fertilizer concentrations and N-levels had significant effects on most yield component, water parameters, fertilizer use efficiency and quality of wheat plants in both seasons. Increasing irrigation levels from 60% to 100% increased all agronomic traits and FUE, but WUE, IWUE and falling number were decreased. The treatment of 400 ppm nano-fertilizer produced high values of all yield parameters, water relation, FUE except falling number. Increasing N-levels from 60 to 100 kg N fed-1 increased all studied traits, but FUE and falling number were deceased. The maximum grain yield (2192.4 and 2251.6), (2026.8 and 2075.7) and (1904.3 and 1964.3 kg fed-1) were produced when 100% of irrigation water, 400ppm of lithovit and 100 kg N fed-1 were applied in the two seasons, respectively. Based on the obtained results, it could be concluded that highest irrigation level of 100%, nano-fertilizer concentration of 400 ppm in combination with Nlevel of 100 kg fed-1 is suitable for Toshka climatic conditions to increase the grain yield and quality of wheat (Triticum durum L.).