The massive use of azoles in agricultural and horticultural production has been described as a determining factor in the emergence of resistant strains, particularly of Aspergillus spp, which pose a significant threat to human and environmental health, according to a recent EU report under the "One Health" approach. This fact is linked to the non-medical use of azoles, according to a recent European Food Safety Authority (EFSA) report under the “One Health” approach. Approximately 120,000 tons of azoles have been placed on the market in the EU/EEA for non-medical uses, mostly as phytosanitary products, according to data analyzed between 2010 and 2021. Some compounds, such as epoxiconazole, used mainly in EU cereal, fruit, vegetables, and other crops, have proved highly resistant. However, because of regulatory advancements, the use of these compounds could be subject to a ban, which would impact the global farming sector. Environmental hotspots for resistance selection have also been identified, including the use and storage of agricultural residues and biocide-treated wood. Therefore, this systematic review aims to evaluate bio-based alternatives, assessing their efficacy, mechanisms of action, impact on harvesting, and limitations. Through a benchmark study with azoles, our work seeks to identify sustainability strategies that reduce the dependence on synthetic fungicides and promote safer and more effective agricultural practices. In addition, regulatory guidelines will be discussed to promote integrated approaches that support robust food security.