In order to recognize the best nutrient supply options for profitable and sustainable production systems, observations were recorded from 2001 to 2020 (20 years) in a long-term fertilizer experiment initiated in 1995–96 with soybean–wheat cropping systems (SWCSs) under irrigated conditions. The experiment comprised of seven treatments including control, organic, inorganic and their combinations. A combined use of 10 Mg farmyard manure (FYM)/ha (M) along with 120 kg N/ha provided statistically (P < 0.05) similar yield and economic benefits to the M + NPK and also provided a positive yield trend (30.0 and 16.2 kg/ha/year) and net return (14.7 and 5.81 US$/ha/year) over the year in both wheat and soybean, respectively. The combined use of organic and chemical fertilizers, provided 32–41% higher production efficiency than their individual use. In contrast, long-term chemical fertilization provided a negative yield trend in both the crops with the highest reduction in sole N-fertilized plots ranged from −39 to −42 kg/ha/year. Water-use efficiency ranged from 3.20 to 12.3 kg/ha/mm in soybean–wheat rotation and increased almost 1.74–3.15 times in wheat and 1.30–1.80 times in soybean due to fertilizer application. A similar trend was observed for water-expense efficiency and remain closely associated with fertilization practice. Long-term chemical fertilizers declined the yield potential of the studied crops while their conjoint application with FYM in the winter season considered as an input efficient approach to sustain the overall productivity and profitability of SWCSs.