Drip fertigation is beneficial to improve crop grain yield (GY), water productivity (WP) and nitrogen use efficiency (NUE), but it is not clear whether drip fertigation can improve economic benefit and how much water and nitrogen should be applied for wheat-maize rotation system in semi-humid and drought-prone regions. A two-year (2018–2020) winter wheat-summer maize rotation field experiment (including twelve drip fertigation treatments (complete combination design of three irrigation (RF: rain-fed, DI: deficit irrigation, 75% ETc, and FI: full irrigation, 100% ETc) and four nitrogen levels (N0: no nitrogen, N1: 85 kg ha−1 for wheat and 90 kg ha−1 for maize, N2: 170 kg ha−1 for wheat and 150 kg ha−1 for maize) and N3: 255 kg ha−1 for wheat and 210 kg ha−1 for maize)) and a conventional practice (Con)) was conducted to explore the response of GY, NUE, WP and net income to different water and nitrogen levels in the Guanzhong Plain of China. The results showed that water and nitrogen application levels had significant effects on GY, NUE, WP and net income of winter wheat and summer maize. For winter wheat, DIN2 (the combination of irrigation and nitrogen) achieved the highest GY (9.2 t ha−1, two-year average), WP (2.11 kg m−3) and net income (11 839 CNY ha−1). For summer maize, the highest GY (11.1 t ha−1), WP (2.32 kg m−3) and net income (14 859 CNY ha−1) were observed at DIN3, RFN3 and DIN2, respectively. For winter wheat-summer maize rotation system, the highest GY (20.2 t ha−1, winter wheat + summer maize, two-year average) and net income (26 698 CNY ha−1) were observed at DIN2; and the highest WP of 2.15 kg m−3 was obtained at RFN3, but had insignificant difference with DIN2 (2.13 kg m−3) (P > 0.05). Therefore, deficit irrigation coupled with 320 kg N ha−1 (170 kg ha−1 for wheat, 150 kg ha−1 for maize) was considered as the best drip fertigation strategy for achieving high GY, WP and net income in winter wheat-summer maize rotation system. Moreover, the response surface methodology was used to determine the optimal water consumption and nitrogen application rate based on binary quadratic regression analysis. The results showed that the GY and net income can synchronously achieve 95~100% maximum values when the water consumption ranged from 434 to 496 mm and 458–500 mm, and the nitrogen application rate ranged from 165 to 211 kg ha−1 and 187–250 kg ha−1 for winter wheat and summer maize, respectively.