Antimicrobial resistance (AMR) due to the prevalence of multidrug-resistant (MDR) pathogens is rapidly increasing worldwide, and the identification of new antimicrobial agents with innovative mechanisms of action is urgently required. Medicinal plants that have been utilised for centuries with minor side effects may hold great promise as sources of effective antimicrobial products. The free-living nematode Caenorhabditis elegans (C. elegans) is an excellent live infection model for the discovery and development of new antimicrobial compounds. However, while C. elegans has widely been utilised to explore the effectiveness and toxicity of synthetic antibiotics, it has not been used to a comparable extent for the analysis of natural products. By screening the PubMed database, we identified articles reporting the use of the C. elegans model for the identification of natural products endowed with antibacterial and antifungal potential, and we critically analysed their results. The studies discussed here provide important information regarding “in vivo” antimicrobial effectiveness and toxicity of natural products, as evaluated prior to testing in conventional vertebrate models, thereby supporting the relevance of C. elegans as a highly proficient model for their identification and functional assessment. However, their critical evaluation also underlines that the characterisation of active phytochemicals and of their chemical structure, and the unravelling of their mechanisms of action represent decisive challenges for future research in this area.