Parasitic helminths are a major constraint on livestock production worldwide, with significant implications for food security and animal and human health. As reliance on conventional anthelmintic drugs becomes increasingly unsustainable due to widespread anthelmintic resistance, chemical residues, and environmental concerns, there is an urgent need for innovative, biologically derived alternatives such as polyunsaturated fatty acids (PUFAs). This review evaluates PUFAs as biologically derived agents that could complement or partially replace conventional dewormers. We integrate molecular, cellular, and in vivo evidence showing that PUFAs exert dual actions: (i) direct effects on parasites, including membrane destabilization, redox dysregulation, and metabolic interference, and (ii) host-directed effects via immune modulation, resolution of inflammation, and tissue repair mediated by specialized pro-resolving lipid mediators. We examine dietary and feed-based sources, discuss the limitations of bioavailability and oxidative stability, and review emerging delivery technologies and bioengineering solutions. Framed within One Health, PUFA-based strategies could reduce chemical inputs, lower residues in food and the environment, and enhance resilience in production systems. Curren barriers include dosage optimization, understanding pharmacokinetics and mechanisms of actions, and generating robust field data. Overall, PUFA-based strategies represent a promising frontier in sustainable parasitology, offering a holistic approach to managing parasitic diseases across species and ecosystems.