The coupling effects of different water and fertilizer combinations on seed cotton yield, water use efficiency and net benefits under drip fertigation were studied in the field of Shihezi during the growing seasons in 2012 and 2013. Multivariate quadratic regression and normalization as well as three different target combinations were used and the optimal water and fertilizer combination that maximized the multi-objective benefits was explored. There were five N-P 2 O 5 -K 2 O fertilizer application rates (150- 60-30, 200-80-40, 250-100-50, 300-120-60, 350-140-70 kg/hm 2 ; denoted as F 150 , F 200 , F 250 , F 300 and F 350 , respectively) and three irrigation levels (W 1 : 60%ET C ; W 2 : 80%ET C ; W 3 : 100%ET C ; ET C represents crop evapotranspiration). The results showed that the coupling of water and fertilizer had significant effects on seed cotton yield, water use efficiency and net benefits. The treatment with low irrigation level (60%ET C ) significantly inhibited seed cotton yield and net benefits, while the treatment with high irrigation level (100%ET C ) significantly increased seed cotton yield and net benefits, but caused lower water use efficiency than that of the treatment with low irrigation level. The combination of irrigation with 100%ET C and fertilizer application rate of 300-120-60 kg/hm 2 (N-P 2 O 5-K 2O) in 2012 produced the highest seed cotton yield, but it did not increase the net benefits. Instead, the combination of irrigation with 100%ET C and fertilizer application rate of 250-100- 50 kg/hm 2 (N- P 2 O 5 - K 2O) produced the highest net benefits in 2012 and 2013. The quadratic regression analysis showed that the multiplication combination exhibited much smaller differences in water and fertilizer inputs in 2012 and 2013 than other combinations. The combination of irrigation with 92%ET C and fertilizer application rate of 278-111-56 kg/hm 2 (N-P 2 O 5 -K 2 O) in 2012, and the combination of irrigation with 90%ET C and fertilizer application rate of 268-107-53 kg/hm 2 (N-P 2 O 5 -K 2 O) in 2013 could maximize the overall multi-objective benefits of seed cotton yield, water use efficiency and net benefits. The results can provide new ideas for the multi-objective management of water and fertilizer in cotton fields under drip fertigation.