The ever-rising trend of nitrate leaching from the agricultural production systems is a major risk to the contamination of ground- and surface-waters and should be addressed. But so far, there has been no study on the reduction of nitrate leaching from saffron fields through intercropping. Saffron growers can make a sustainable use of the saffron inter-row spaces through the strategy of winter-wheat/saffron base intercropping system to reduce nitrate leaching. During four years of study, in a set of lysimeters, effects of two cropping systems (saffron mono-cropping and saffron–wheat intercropping), application of two sources of nitrogen (organic cow manure and chemical granular urea) and four irrigation regimes [40, 60, 80, and 100% of the standard crop evapotranspiration (ETc)] on plant nitrogen and phosphorus uptake, nitrogen leaching and nitrogen and phosphorus efficiencies were investigated. The optimum irrigation regime was experienced at 60% ETc (with irrigation application efficiency of 60%, equivalent to 100%ETc) where the highest saffron and wheat nutrient (nitrogen and phosphorus) uptake, nutrient (nitrogen and phosphorus) harvest indices, nutrient acquisition and use efficiencies, corm, saffron, and grain yields and lowest nitrogen loss was achieved. Moreover, manure application indicated 12, 42, 50 and 46% lower amounts of drained water, leachate nitrate nitrogen concentration, total leached nitrogen and N losses (other than N leaching), respectively, in comparison to the urea source of nitrogen showing the lower risk of groundwater nitrate pollution. Manure application showed 9, 8 and 9% increase in the concentration of corm nitrogen, phosphorus and protein, respectively, in comparison to urea application treatment. Saffron corm and stigma yields, irrigation and economic water productivities, corm nitrogen use efficiency and saffron-plant-nitrogen-acquisition efficiency in manure application surpassed respectively by 21, 25, 20, 17, 39 and 49% compared with the chemical source of nitrogen. Intercropping showed 10, 11, 23 and 64% lower amounts of drained water, nitrate concentration in drainage water, seasonal leached nitrate and N losses (other than N leaching), respectively compared to saffron sole cropping which reduces the risk of groundwaters nitrate contamination. For all the experimental treatments, empirical regression models were derived for estimation of seasonal leached nitrate based on the seasonal drained water. Intercropping saffron with winter wheat, application of organic cow manure and adopting irrigation regime of 60% ETc is an innovative system of saffron production which mitigates the risk of groundwater nitrate contamination and increases irrigation and economic water productivities. Saffron growers can make sustainable and clean use of the inter-row spaces of the saffron crop to grow winter wheat in order to obtain higher economic water productivity and lower groundwater nitrate pollution, and it is highly recommended to maintain a sustainable environment.