This chapter focuses on the role of Caenorhabditis elegans as a bridging model in nanotoxicology and nanosafety research. With its simple multicellular structure, well-characterized genetics, low maintenance costs, short life cycle, and suitability for high-throughput screening, C. elegans is effective for evaluating nanoparticle toxicity across various exposure scenarios, including acute and chronic treatments. The chapter examines key physiological endpoints—such as survival rates, growth, reproduction, and behavior—and employs mutant and transgenic strains alongside advanced omics technologies to investigate the molecular pathways affected by nanoparticle exposure, particularly oxidative stress, genotoxicity, and neurotoxicity. By integrating multi-endpoint assessments and behavioral investigations, C. elegans provides valuable insights into the safety and potential risks of nanomaterials, contributing to a broader understanding of nanotoxicology in alignment with the ‘One Health’ framework.