The unsustainable use of natural resources, in particular soil degradation and pollution, is one of the main factors contributing to the climate and biodiversity crisis. The European Union has outlined a new European Green Deal, whose objectives include increasing the overall quality of the agri-food chain in relation to environmental sustainability, focusing on reducing the use of pesticides and increasing the share of organic in overall production. A Nexus thinking perspective is applied to analyse this topic over a 50-year time horizon (2010–2060) for the agricultural system of the Basilicata Region (Southern Italy), represented by the TIMES Land-WEF, an optimizing, bottom-up energy-technology model, built to investigate the interactions and interrelations between water, energy food and land. The novelty of this modelling approach is the choice of land use as the guiding parameter of the optimization process. The main objectives of the Farm to Fork Strategy are modelled as system constraints and the scenario analysis allows to characterise their effects on the evolution of the agricultural system over the examined time. The results show that the pesticide reduction constraint leads to an increase in land use by organic crops from 24.6 % to 32.4 % in 2060. In particular, this is due to the increased contribution of cereal, forage, olive growing crops, permanent meadows and pastures, which lead to a 46 % reduction in irrigation water consumption. On the other hand, the reduction in inorganic fertilizers is not accompanied by a significant increase in organic crops, but resulted in the reduction of cereal crops.