Innate immunity, as a significant defense system of the body, plays a key role in allergic reactions, but the mechanism of how food allergens trigger innate immune signaling is still unclear. Ovalbumin (OVA) is a model allergen in food allergy studies. Previous studies by our group have demonstrated that the innate immunity of Caenorhabditis elegans (C. elegans) elicited by OVA treatment was related to the insulin/insulin-like growth factor-1 signaling (IIS) pathway, but the details remain unknown. Therefore, in this study, the molecular mechanism of innate immune signaling transduction of C. elegans stimulated by OVA was determined using genetic mutations as well as RT-PCR, GFP fluorescence visualization monitoring, and slow-killing experiments. Results showed that the expression levels of DAF-16-class-I/II genes in the IIS pathway were significantly changed in C. elegans after OVA treatment, and the upstream gene daf-2 played an important role, which up-regulated the levels of DAF-16-class-II genes dod-22 and F55G11.8 by the daf-2-pqm-1 pathway, and down-regulated the level of DAF-16-class-I gene thn-2 by the daf-2-daf-16 pathway. Moreover, the upstream genes daf-2 and nhr-14, and the transcription factors DAF-16, PQM-1, and SKN-1 in the IIS pathway all participated in the up-regulations of DAF-16-class-II genes dod-17, dod-24, and F55G11.2. In conclusion, details of OVA activating innate immunity in C. elegans through the IIS pathway are reported here, and the results can be further extrapolated to mammals, which will contribute to a better understanding of the mechanism of the occurrence of food allergic reactions from the perspective of innate immunity.