Agricultural practices are causing a variety of environmental impacts such as emissions of ammonia (NH3) and greenhouse gases (GHG), and leaching and runoff of nutrients to groundwater and surface water. Measures need to be taken to achieve environmental targets set in European agreements and directives, such as the Birds and Habitats Directives, Nitrates Directive, Water Framework Directive and Fit for 55 package. To explore solutions for these issues an integral approach is needed, in which synergies between measures are included and pollution swapping is avoided. In addition, spatial interaction needs to be included because the environmental impacts are related to the spatial distribution of nature sites, farming systems, soil type and hydrology. We performed a regionalised approach for the Netherlands using a suite of models to simulate the effect of agricultural measures on manure and fertilizer distribution, emissions of NH3 and GHG, nitrogen (N) deposition on nature, nitrate (NO3−) leaching to groundwater, N and phosphorus (P) losses to surface waters, and soil carbon (C) sequestration. A mix of structural, technical and management measures was evaluated to achieve targets on both regional and national level for a regionalised approach and a more generic (national) approach. Results show that the regionalised approach is more beneficial, especially for water quality improvement and N deposition reduction and to a lesser extend for the mitigation of GHG emissions and NO3− leaching. When all measures are fully implemented, the 2030 targets for NO3− and N deposition can be attained, but the targets for surface water and climate mitigation cannot be met.