Zearalenone (ZEA), a mycotoxin, poses a significant global hazard to human and animal health. Natural products (NPs) have shown promise for mitigating the adverse effects of ZEA owing to their diverse functional activities. However, the current challenge lies in the absence of an efficient strategy for systematic screening and identification of NPs that can effectively protect against ZEA-induced toxicity. This study describes a phenotype-based screening strategy for screening NP libraries and discovering more effective compounds to mitigate or counteract the adverse consequences of ZEA exposure in animals. Using this strategy, we initially identified 96 NPs and evaluated the potency and efficacy of two effective candidate compounds, fraxetin, and hydroxytyrosol, based on embryonic phenotype and locomotor activity using a scoring system and the TCMacro method. Furthermore, we performed transcriptome and protein−protein interaction (PPI) network analyses to extract two mRNA signatures to query the Connectivity Map (CMap) database and predict NPs. The predicted NPs showed the potential to reverse the gene expression profiles associated with ZEA toxicity. Consequently, we further screened these compounds using our model, which indicated that hispidin, daphnetin, and riboflavin exhibit promising in vivo efficacy in zebrafish. Notably, throughout the process, fraxetin consistently stood out as the most promising NP. Biological pathway analysis and functional verification revealed that fraxetin completely reversed the toxic effects of ZEA at very low doses. This was achieved by repairing damaged cell apoptosis, modifying the cell cycle pathway, and preventing senescence induction, indicating good application potential. Overall, we demonstrated that this integration strategy can be successfully applied to effectively discover potential antidotes.