Per- and polyfluoroalkyl substances (PFASs) are synthetic fluorinated chemicals known for their functional head group and fluorinated carbon-chain tail. Their exceptional resistance to water, oil, and stains, along with high-temperature tolerance, makes PFAS widely used in industries such as aerospace, construction, electronics, automotive, medical devices, firefighting foams, cosmetics, and waterproof products like carpets, jackets, paper, and nonstick cookware, to name a few. This chapter offers a comprehensive overview of PFAS contamination through a One Health perspective, focusing on their global distribution, persistence, and significant health impacts on humans. We investigated the various sources of PFAS contamination globally, examining its environmental fate, transport mechanisms, and key environmental factors influencing PFAS mobility and bioaccumulation potential, which have raised critical public health concerns and prompted government interventions, necessitating international cooperation and regulatory action. Key topics include PFAS contamination pathways, human exposure through contaminated food and water, with associated health risks such as various cancers, immune dysfunction, reproductive and hormonal disorders (like PCOS and infertility), metabolic and cardiovascular issues, and potential neurological and developmental disorders. The chapter also reviews current methods for PFAS removal and degradation, examining the environmental, technical, and economic challenges these methods face. Finally, we highlight collaborative global policies and programs, including initiatives by agencies like the U.S. Environmental Protection Agency (EPA).