The presence of organic contaminants in agroecosystems poses a significant risk to ecosystem health and food safety. These xenobiotics enter soils through sewage sludge application, reclaimed wastewater irrigation, and livestock manure, where they disrupt soil microbial diversity and functionality and impair key edaphic processes such as nutrient cycling and organic matter decomposition. Their persistence enables accumulation in plant tissues and biomagnification across trophic levels, posing risks to ecosystem health and food safety. A persistence study evaluated the behaviour of two pesticides (trifloxystrobin and pendimethalin) and two pharmaceutical products (mebendazole and venlafaxine) in a Mediterranean Alfisol soil type, as well as the effect of adding biowaste compost on their dissipation. A microcosm assay monitored their concentrations over 21 days. Determination of these compounds in the soil matrix was performed using QuEChERSER liquid-phase extraction method followed by UHPLC-MS/MS quantification. Trifloxystrobin showed rapid degradation in soil, while mebendazole exhibited high persistence in unamended soil and venlafaxine showed very high persistence in both soils. Pendimethalin dissipation was intermediate. Compost significantly accelerated the degradation of pendimethalin and mebendazole and also promoted venlafaxine degradation. These results reinforce the need to control xenobiotic contamination in intensive agricultural systems. In the Valencian Community, uptake and accumulation of organic contaminants in plant tissues has been observed, threatening food safety through bioaccumulation and biomagnification. The validation of soil bioremediation strategies using quality organic amendments like compost, together with robust analytical methods (QuEChERSER-UHPLC-MS/MS), is key to generating information that supports specific regulations and healthy soils to mitigate the ecotoxicological effects of these contaminants.