Overuse of N fertilizers in crops has induced the disruption of the N cycle, triggering the release of reactive N (Nr) to the environment. Several EU policies have been developed to address this challenge, establishing targets to reduce agricultural Nr losses. Their achievement could be materialized through the introduction of fertilizing innovations such as incorporating fertilizer into soils, using urease inhibitors, or by adjusting N inputs to crop needs that could impact in both yields and environment. The Murcia region (southeastern Spain) was selected as a paradigmatic case study, since overfertilization has induced severe environmental problems in the region in the last decade, to assess the impact of a set of 8 N fertilizing alternatives on crop yields and environmental Nr losses. Some of these practices imply the reduction of N entering in crops. We followed an integrated approach analyzing the evolution of the region in the long-term (1860–2018) and considering nested spatial- (from grid to region) and systems scales (from crops to the full agro-food system). We hypothesized that, even despite reduction of N inputs, suitable solutions for the abatement of Nr can be identified without compromising crop yields. The most effective option to reduce Nr losses was removing synthetic N fertilizers, leading to 75% reductions in N surpluses mainly due to a reduction of 64% of N inputs, but with associated yield penalties (31%–35%). The most feasible alternative was the removal of urea, resulting in 19% reductions of N inputs, 15%–21% declines in N surplus, and negligible yield losses. While these measures are applied at the field scale, their potential to produce a valuable change can only be assessed at regional scale. Because of this, a spatial analysis was performed showing that largest Nr losses occurred in irrigated horticultural crops. The policy implications of the results are discussed.