Plastics are ubiquitous pollutants in atmospheric, terrestrial, and aquatic ecosystems due to their widespread use and environmental persistence. Plastic additives, intentionally incorporated to enhance the functionality of plastics, leach into the environment during plastic degradation, posing significant risks to ecological and human health. The limited understanding of these chemicals across the plastic life cycle hinders effective regulation and comprehensive product safety evaluations. To address these challenges, we employed a toxicogenomics-driven, data-centric approach to investigate the toxicological impacts of plastic additives through the Adverse Outcome Pathway (AOP) framework. A curated dataset of 6,470 plastic additives was classified into ten priority use sectors, such as food packaging, personal care products, and agriculture. By integrating toxicogenomic and biological endpoint data from five exposome-relevant resources, associations were established between 1,287 additives and 322 high-quality AOPs documented in AOP-Wiki. These associations facilitated the development of a stressor-centric AOP network that categorizes additives by use sectors and organizes AOPs under 27 disease categories based on their adverse outcomes. The utility of this network was demonstrated through the analysis of three priority additives: benzo[a]pyrene (B[a]P), bisphenol A (BPA), and bis(2-ethylhexyl) phthalate (DEHP). Published experimental evidence highlighted toxicity pathways relevant to human and ecological health, originating from molecular interactions and progressing through cellular and tissue-level changes to ultimately manifest as adverse effects at the organ, individual or population levels. Through this work, we introduced the first stressor-centric AOP network for plastic additives, providing critical insights into toxicity mechanisms, prevalent adverse outcomes, and risk assessment frameworks. By advancing regulatory decision-making, these findings contribute toward the realization of a toxic-free circular economy for plastics.