Biodegradable polymers are acclaimed for their potential to replace petrochemical plastics; however, they require comprehensive evaluation of their environmental and safety impacts. This chapter integrates toxicity testing methods with mechanistic degradation analysis and life-cycle assessment to evaluate both synthetic polymers such as PLA, PCL, PBS, and PBAT, and natural polymers such as starch, cellulose, chitosan, and PHAs in packaging applications, as well as biomedical, agricultural, and marine settings. Our research examines the degradation pathways involving abiotic and biotic factors and investigates micro- and nanoplastic production while tracking additive migration and leachate profiles through a comprehensive integration of in vitro studies with in vivo findings, alongside ecotoxicity assessments and USEtox-related life-cycle analyses. Trade-offs between greenhouse gas mitigation, land use, and potential ecotoxicity become evident through comparative case studies, policy analyses, and safe-by-design principles. Current research priorities emphasize standardized microplastic testing methods, AI-based hazard forecasting, and uniform global standards to promote circular polymer economies.