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Their resistance to degradation and global dissemination demand an integrated One Health framework to address their complex, interdependent risks across ecosystems, wildlife, and public health. This review synthesizes current knowledge on PFAS, highlighting their anthropogenic origins, environmental persistence, and global dispersion. Common exposure pathways, such as dietary intake, contaminated drinking water, and maternal transfer, lead to convergent toxicological outcomes across species, including immunotoxicity, reproductive and developmental impairments, and carcinogenicity, validating the use of cross-species data in risk assessment and reinforcing the need for integrated protective strategies. Vulnerable human populations and wildlife face disproportionate risks, with the latter acting as both sentinels and exposure sources. Despite regulatory efforts, the ongoing use and development of replacement compounds sustain PFAS as a global concern. Effectively addressing this challenge requires a coordinated, cross-sectoral strategy that integrates environmental monitoring, transdisciplinary research, and harmonized regulatory frameworks. 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