Epidemiological evidence has shown that the regular ingestion of vegetables and fruits is associated with reduced risk of developing chronic diseases. The introduction of the 3Rs (replacement, reduction, and refinement) principle into animal experiments has led to the use of valid, cost-effective, and efficient alternative and complementary invertebrate animal models which are simpler and lower in the phylogenetic hierarchy. Caenorhabditis elegans (C. elegans), a nematode with a much simpler anatomy and physiology compared to mammals, share similarities with humans at the cellular and molecular levels, thus making it a valid model organism in neurotoxicology. This review explores the versatility of C. elegans in elucidating the neuroprotective mechanisms elicited by food bioactive compounds against neurotoxic effects of food- and environmental-related contaminants. Several signaling pathways linked to the molecular basis of neuroprotection exerted by bioactive compounds in chemically induced or transgenic C. elegans models of neurodegenerative diseases are also discussed. Specifically, the modulatory effects of bioactive compounds on the DAF-16/FoxO and SKN-1/Nrf2 signaling pathways, stress resistance- and autophagy-related genes, and antioxidant defense enzyme activities were highlighted. Altogether, C. elegans represent a valuable model in nutritional neuroscience for the identification of promising neuroprotective agents and neurotherapeutic targets which could help in overcoming the limitations of current therapeutic agents for neurotoxicity and neurodegenerative diseases.