Various anthropogenic activities, the expansion of maritime transportation and industries, and the advancements in agricultural modalities have contributed significantly towards the production of emerging pollutants (EPs) into the environment, which has emerged as a serious threat to natural ecosystems. The vast and diverse array of EPs released from soil, groundwaters, surface water, and other potentially contaminated sources presents a major threat not only to the stability of the marine environment but also to human health. Several traditional toxicity testing methods have been reported to date, but they often fall short due to the sheer number and diverse nature of these chemicals. However, the Tox-21 framework with its high-throughput screening (HTS) and advanced computational modeling capabilities has emerged as a powerful tool for navigating this complex challenge. Given the extensive array of chemicals in use, it is essential to identify and prioritize chemical compounds that have the potential to induce biological impacts. This necessity underscores the utility of predictive Tox-21 methods such as chemical category, read-across, substructural alerts, quantitative structure-activity relationship (QSAR), molecular docking, molecular dynamics simulations, pharmacophore, machine learning (ML), toxicogenomics, and chemoinformatic approaches for the assessment of EPs in the marine environment. As far as the application of these methods to marine pollutants particularly EPs is concerned, QSAR, ML, and molecular docking-based studies of diverse organic chemicals, pharmaceutical agents, biocides, personal care products (PCPs), and microplastics are the most frequently reported. Notably, QSAR- and ML-based approaches have been proven to be highly significant in predicting the toxicity associated with EPs in the marine environment. Towards this, the book chapter will provide an overview of the escalating issue of EPs in marine ecosystems and the necessity for advanced predictive methods. In addition, this chapter will particularly advance the current knowledge base on the presence, origin, and consequences of EPs, with a major focus on enhancing analytical methods for detecting a broader range of contaminants and establishing new guidelines for the safety of human health and the marine environment. Furthermore, an in-depth review of the Tox-21 methods and their applications in predicting the toxicity of EPs in marine environments will be presented herein.